Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use

ABSTRACT

Indazole compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction and thereby modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.09/983,786, filed Oct. 25, 2001, now U.S. Pat. No. 6,531,491 which is adivisional of U.S. application Ser. No. 09/609,335, filed Jun. 30, 2000,now abandoned, which claims the benefit of U.S. Provisional ApplicationNo. 60/142,130, filed Jul. 2, 1999, hereby incorporated by reference intheir entireties for all purposes.

FIELD OF THE INVENTION

This invention is directed to indazole compounds that mediate and/orinhibit the activity of certain protein kinases, and to pharmaceuticalcompositions containing such compounds. The invention is also directedto the therapeutic or prophylactic use of such compounds andcompositions, and to methods of treating cancer as well as other diseasestates associated with unwanted angiogenesis and/or cellularproliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION

Protein kinases are a family of enzymes that catalyze phosphorylation ofthe hydroxyl group of specific tyrosine, serine, or threonine residuesin proteins. Typically, such phosphorylation dramatically perturbs thefunction of the protein, and thus protein kinases are pivotal in theregulation of a wide variety of cellular processes, includingmetabolisim, cell proliferation, cell differentiation, and cellsurvival. Of the many different cellular functions in which the activityof protein kinases is known to be required, some processes representattractive targets for therapeutic intervention for certain diseasestates. Two examples are angiogenesis and cell-cycle control, in whichprotein kinases play a pivotal role; these processes are essential forthe growth of solid tumors as well as for other diseases.

Angiogenesis is the mechanism by which new capillaries are formed fromexisting vessels. When required, the vascular system has the potentialto generate new capillary networks in order to maintain the properfunctioning of tissues and organs. In the adult, however, angiogenesisis fairly limited, occurring only in the process of wound healing andneovascularization of the endometrium during menstruation. See Merenmieset al., Cell Growth & Differentiation, 8, 3-10 (1997). On the otherhand, unwanted angiogenesis is a hallmark of several diseases, such asretinopathies, psoriasis, rheumatoid arthritis, age-related maculardegeneration (AMD), and cancer (solid tumors). Folkman, Nature Med., 1,27-31 (1995). Protein kinases which have been shown to be involved inthe angiogenic process include three members of the growth factorreceptor tyrosine kinase family: VEGF-R2 (vascular endothelial growthfactor receptor 2, also known as KDR (kinase insert domain receptor) andas FLK-1); FGF-R (fibroblast growth factor receptor); and TEK (alsoknown as Tie-2).

VEGF-R2, which is expressed only on endothelial cells, binds the potentangiogenic growth factor VEGF and mediates the subsequent signaltransduction through activation of its intracellular kinase activity.Thus, it is expected that direct inhibition of the kinase activity ofVEGF-R2 will result in the reduction of angiogenesis even in thepresence of exogenous VEGF (see Strawn et al., Cancer Research, 56,3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which failto mediate signal transduction. Millauer et al., Cancer Research, 56,1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function inthe adult beyond that of mediating the angiogenic activity of VEGF.Therefore, a selective inhibitor of the kinase activity of VEGF-R2 wouldbe expected to exhibit little toxicity.

Similarly, FGF-R binds the angiogenic growth factors aFGF and bFGF andmediates subsequent intracellular signal transduction. Recently, it hasbeen suggested that growth factors such as bFGF may play a critical rolein inducing angiogenesis in solid tumors that have reached a certainsize. Yoshiji et al., Cancer Research, 57, 39243928 (1997). UnlikeVEGF-R2, however, FGF-R is expressed in a number of different cell typesthroughout the body and may or may not play important roles in othernormal physiological processes in the adult. Nonetheless, systemicadministration of a small-molecule inhibitor of the kinase activity ofFGF-R has been reported to block bFGF-induced angiogenesis in micewithout apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904(1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase expressedonly on endothelial cells which has been shown to play a role inangiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

As a result of the above-described developments, it has been proposed totreat angiogenesis by the use of compounds inhibiting the kinaseactivity of VEGF-R2, FGF-R, and/or TEK. For example, WIPO InternationalPublication No. WO 97/34876 discloses certain cinnoline derivatives thatare inhibitors of VEGF-R2, which may be used for the treatment ofdisease states associated with abnormal angiogenesis and/or increasedvascular permeability such as cancer, diabetes, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restinosis, autoimmune diseases, acuteinflammation, and ocular diseases with retinal vessel proliferation.

Phosphorylase kinase activates glycogen phosphorylase, thus increasingglycogen breakdown and hepatic glucose release. Hepatic glucoseproduction is disregulated in type 2 diabetes, and is the primary causeof fasting hyperglycemia, which results in many of the secondarycomplications afflicting these patients. Thus, reduction in glucoserelease from the liver would lower elevated plasma glucose levels.Inhibitors of phosphorylase kinase should therefore decreasephosphorylase activity and glycogenolysis, thus reducing hyperglycemiain patients.

Another physiological response to VEGF is vascular hyperpermeability,which has been proposed to play a role in the early stages ofangiogenesis. In ischemic tissues, such as those occurring in the brainof stroke victims, hypoxia trigger VEGF expression, leading to increasedvascular permeability and ultimately edema in the surrounding tissues.In a rat model for stroke, it has been shown by van Bruggen et al., J.Clinical Invest., 104, 1613-20 (1999) that administration of amonoclonal antibody to VEGF reduces the infarct volume. Thus, inhibitorsof VEGFR are anticipated to be useful for the treatment of stroke.

In addition to its role in angiogenesis, protein kinases also play acrucial role in cell-cycle control. Uncontrolled cell proliferation isthe insignia of cancer. Cell proliferation in response to variousstimuli is manifested by a de-regulation of the cell division cycle, theprocess by which cells multiply and divide. Tumor cells typically havedamage to the genes that directly or indirectly regulate progressionthrough the cell division cycle.

Cyclin-dependent kinases (CDKs) are serine-threonine protein kinasesthat play critical roles in regulating the transitions between differentphases of the cell cycle. See, e.g., the articles compiled in Science,274, 1643-1677 (1996). CDK complexes are formed through association of aregulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E)and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, andCDK6). As the name implies, the CDKs display an absolute dependence onthe cyclin subunit in order to phosphorylate their target substrates,and different kinase/cyclin pairs function to regulate progressionthrough specific phases of the cell cycle.

It is CDK4 complexed to the D cyclins that plays a critical part ininitiating the cell-division cycle from a resting or quiescent stage toone in which cells become committed to cell division. This progressionis subject to a variety of growth regulatory mechanisms, both negativeand positive. Aberrations in this control system, particularly thosethat affect the function of CDK4, have been implicated in theadvancement of cells to the highly proliferative state characteristic ofmalignancies, particularly familial melanomas, esophageal carcinomas,and pancreatic cancers. See, e.g., Kamb, Trends in Genetics, 11, 136-140(1995); Kamb et al., Science, 264, 436440 (1994).

Myriad publications describe a variety of chemical compounds usefulagainst a variety of therapeutic targets. For example. WIPOInternational Publication Nos. WO 99/23077 and WO 99/23076 describeindazole-containing compounds having phosphodiesterase type IVinhibitory activity produced by an indazole-for-catechol bioisosterereplacement. U.S. Pat. No. 5,760,028 discloses heterocycles including3-[1-[3-(imidazolin-2-ylamino)propyl]indazol-5-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid, which are useful as antagonists of the α_(v)β₃ integrin andrelated cell surface adhesive protein receptors. WIPO InternationalPublication No. WO 98/09961 discloses certain indazole derivatives andtheir use as inhibitors of phosphodiesterase (PDE) type IV or theproduction of tumor necrosis factor (TNF) in a mammal. Recent additionsto the virtual library of known compounds include those described asbeing anti-proliferative therapeutic agents that inhibit CDKs. Forexample, U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acidencoding an inhibitor of CDK6, and European Patent Publication No. 0 666270 A2 describes peptides and peptide mimetics that act as inhibitors ofCDK1 and CDK2. WIPO International Publication No. WO 97/16447 disclosescertain analogs of chromones that are inhibitors of cyclin-dependentkinases, in particular of CDK/cyclin complexes such as CDK4/cyclin D1,which may be used for inhibiting excessive or abnormal cellproliferation, and therefore for treating cancer. WIPO InternationalPublication No. WO 99/21845 describes 4-aminothiazole derivatives thatare useful as CDK inhibitors.

There is still a need, however, for small-molecule compounds that may bereadily synthesized and are effective in inhibiting one or more CDKs orCDK/cyclin complexes. Because CDK4 may serve as a general activator ofcell division in most cells, and complexes of CDK4 and D-type cyclinsgovern the early G₁ phase of the cell cycle, there is a need foreffective inhibitors of CDK4, and D-type cyclin complexes thereof, fortreating one or more types of tumors. Also, the pivotal roles of cyclinE/CDK2 and cyclin B/CDK1 kinases in the G₁/S phase and G₂/M transitions,respectively, offer additional targets for therapeutic intervention insuppressing deregulated cell-cycle progression in cancer.

Another protein kinase, CHK1, plays an important role as a checkpoint incell-cycle progression. Checkpoints are control systems that coordinatecell-cycle progression by influencing the formation, activation andsubsequent inactivation of the cyclin-dependent kinases. Checkpointsprevent cell-cycle progression at inappropriate times, maintain themetabolic balance of cells while the cell is arrested, and in someinstances can induce apoptosis (programmed cell death) when therequirements of the checkpoint have not been met. See, e.g., O'Connor,Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997);Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al.,Science, 246, 629-634 (1989).

One series of checkpoints monitors the integrity of the genome and, uponsensing DNA damage, these “DNA damage checkpoints” block cell-cycleprogression in G₁ and G₂ phases, and slow progression through S phase.O'Connor, Cancer Surveys, 29, 151-182 (1997); Hartwell et al., Science,266, 1821-1828 (1994). This action enables DNA repair processes tocomplete their tasks before replication of the genome and subsequentseparation of this genetic material into new daughter cells takes place.Importantly, the most commonly mutated gene in human cancer, the p53tumor suppressor gene, produces a DNA damage checkpoint protein thatblocks cell-cycle progression in G₁ phase and/or induces apoptosis(programmed cell death) following DNA damage. Hartwell et al., Science,266, 1821-1828 (1994). The p53 tumor suppressor has also been shown tostrengthen the action of a DNA damage checkpoint in G₂ phase of the cellcycle. See, e.g., Bunz et al., Science, 28, 1497-1501 (1998); Winters etal., Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15, 3025-3035(1997).

Given the pivotal nature of the p53 tumor suppressor pathway in humancancer, therapeutic interventions that exploit vulnerabilities inp53-defective cancer have been actively sought. One emergingvulnerability lies in the operation of the G₂ checkpoint in p53defective cancer cells. Cancer cells, because they lack G₁ checkpointcontrol, are particularly vulnerable to abrogation of the last remainingbarrier protecting them from the cancer-killing effects of DNA-damagingagents: the G₂ checkpoint. The G₂ checkpoint is regulated by a controlsystem that has been conserved from yeast to humans. Important in thisconserved system is a kinase, CHK1, which transduces signals from theDNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2kinase, which promotes mitotic entry. See, e.g., Peng et al., Science,277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997).Inactivation of CHK1 has been shown to both abrogate G₂ arrest inducedby DNA damage inflicted by either anticancer agents or endogenous DNAdamage, as well as result in preferential killing of the resultingcheckpoint defective cells. See, e.g., Nurse, Cell, 91, 865-867 (1997);Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363,368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell, 5, 147-160(1994).

Selective manipulation of checkpoint control in cancer cells couldafford broad utilization in cancer chemotherapeutic and radiotherapyregimens and may, in addition, offer a common hallmark of human cancer“genomic instability” to be exploited as the selective basis for thedestruction of cancer cells. A number of factors place CHK1 as a pivotaltarget in DNA-damage checkpoint control. The elucidation of inhibitorsof this and functionally related kinases such as Cds1/CHK2, a kinaserecently discovered to cooperate with CHK1 in regulating S phaseprogression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka,Science, 282, 1893-1897 (1998)), could provide valuable new therapeuticentities for the treatment of cancer.

Integrin receptor binding to ECM initiates intracellular signalsmediated by FAK (Focal Adhesion Kinase) that are involved in cellmotility, cellular proliferation, and survival. In human cancers, FAKoverexpression is implicated in tumorigenesis and metastatic potentialthrough its role in integrin mediated signaling pathways.

Tyrosine kinases can be of the receptor type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). At least one of the non-receptor protein tyrosinekinases, namely, LCK, is believed to mediate the transduction in T-cellsof a signal from the interaction of a cell-surface protein (Cd4) with across-linked anti-Cd4 antibody. A more detailed discussion ofnon-receptor tyrosine kinases is provided in Bolen, Oncogene, 8,2025-2031 (1993), which is incorporated herein by reference.

In addition to the protein kinases identified above, many other proteinkinases have been considered to be therapeutic targets, and numerouspublications disclose inhibitors of kinase activity, as reviewed in thefollowing: McMahon et al, Oncologist, 5, 3-10 (2000); Holash et al.,Oncogene, 18, 5356-62 (1999); Thomas et al., J. Biol. Chem., 274,3668492 (1999); Cohen, Curr. Op. Chem Biol., 3, 459-65 (1999); Klohs etal., Curr. Op. Chem Biol., 10, 54449 (1999); McMahon et al., CurrentOpinion in Drug Discovery & Development, 1, 131-146 (1998); Strawn etal., Exp. Opin. Invest. Drugs, 7, 553-573 (1998). WIPO InternationalPublication WO 00/18761 discloses certain substituted 3-cyanoquinolinesas protein kinase inhibitors.

There is still a need, however, for effective inhibitors of proteinkinases. Moreover, as is understood by those skilled in the art, it isdesirable for kinase inhibitors to possess both high affinity for thetarget kinase or kinases as well as high selectivity versus otherprotein kinases.

SUMMARY OF THE INVENTION

Thus, an objective of the invention is to discover potent inhibitors ofprotein kinases. Another objective of the invention is to discovereffective kinase inhibitors having a strong and selective affinity forone or more particular kinases.

These and other objectives of the invention, which will become apparentfrom the following description, have been achieved by the discovery ofthe indazole compounds, pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts thereof (such compounds, prodrugs, metabolites and salts arecollectively referred to as “agents”) described below, which modulateand/or inhibit the activity of protein kinases. Pharmaceuticalcompositions containing such agents are useful in treating diseasesmediated by kinase activity, such as cancer, as well as other diseasestates associated with unwanted angiogenesis and/or cellularproliferation, such as diabetic retinopathy, neovascular glaucoma,rheumatoid arthritis, and psoriasis. Further, the agents haveadvantageous properties relating to the modulation and/or inhibition ofthe kinase activity associated with VEGF-R, FGF-R, CDK complexes, CHK1,LCK, TEK, FAK, and/or phosphorylase kinase.

In a general aspect, the invention relates to compounds of the FormulaI:

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═CH—R³ or CH═N—R³ where R³ is a        substituted or unsubstituted alkyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; and    -   R² is a substituted or unsubstituted aryl, heteroaryl, or Y—X,        where Y is O, S, C═CH₂, C═O, S═O, SO₂, alkylidene, NH, or        N-(C₁-C₈ alkyl), and X is substituted or unsubstituted Ar,        heteroaryl, NH-(alkyl), NH-(cycloalkyl), NH-(heterocycloalkyl),        NH(aryl), NH(heteroaryl), NH-(alkoxyl), or NH-(dialkylamide),        where Ar is aryl;

The invention is also directed to pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of the compounds of Formula I. Advantageous methods of making thecompounds of the Formula I are also described.

In another general aspect, the invention relates to compounds of theFormula 1(a):

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═CH—R³ or CH═N—R³ where R³ is a        substituted or unsubstituted alkyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; and    -   R² is a substituted or unsubstituted aryl or Y—Ar, where Y is O,        S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈ alkyl), and        Ar is a substituted or unsubstituted aryl.

The invention is also directed to pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of the compounds of Formula I(a). Advantageous methods of makingthe compounds of the Formula I(a) are also described.

In one preferred general embodiment, the invention relates to compoundshaving the Formula II:

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═H—R³ or CH═N—R³, where R³ is a        substituted or unsubstituted alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl;    -   R⁴ and R⁷ are each independently hydrogen, OH, halo, C₁-C₈        alkyl, C₁-C₈ alkoxy, C₁-C₈ alkenyl, aryloxy, thioaryl, CH₂—OH,        CH₂—O— (C₁-C₈ alkyl), CH₂—O-aryl, CH₂—S—(C₁-C₈ alkyl), or        CH₂—S-aryl;    -   R⁵ and R⁶ are each independently hydrogen, OH, halo, Z-alkyl,        Z-aryl, or Z-CH₂CH═CH₂, where Z is O, S, NH, or CH₂, and the        alkyl and aryl moieties of Z-alkyl and Z-aryl are each        optionally substituted;    -   and pharmaceutically acceptable prodrugs, pharmaceutically        active metabolites, and pharmaceutically acceptable salts        thereof.

In a preferred embodiment of Formula H: R¹ is a substituted orunsubstituted bicyclic heteroaryl, or a group of the formula CH═CH—R³where R³ is a substituted or unsubstituted aryl or heteroaryl; R⁴ and R⁷are each independently hydrogen or C₁-C₈ alkyl; and R⁵ and R⁶ are eachindependently halo, Z-alkyl, or Z-CH₂CH═CH₂, where Z is O or S.

In another preferred general embodiment, compounds of the invention areof Formula m:

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═CH—R³ or CH═N—R³, where R³ is a        substituted or unsubstituted alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl;    -   Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈        alkyl);    -   R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;    -   R¹⁰ is independently selected from hydrogen, halogen, and        lower-alkyl;        and pharmaceutically acceptable prodrugs, pharmaceutically        acceptable metabolites, and pharmaceutically acceptable salts        thereof.

More preferably, in Formula m: R¹ is a substituted or unsubstitutedbicyclic heteroaryl, or a group of the formula CH═CH—R³ where R³ is asubstituted or unsubstituted aryl or heteroaryl; Y is O, S, C═CH₂, C═O,NH, or N—(C₁-C₈ alkyl); R⁸ is a substituted or unsubstituted aryl,heteroaryl, alkyl, and alkenyl, and R¹⁰ is hydrogen or halogen.

In another preferred general embodiment, compounds of the invention areof Formula [(a):

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═CH—R³ or CH═N—R³, where R³ is a        substituted or unsubstituted alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl;    -   Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N-(C₁-C₈        alkyl);    -   R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;        and pharmaceutically acceptable prodrugs, pharmaceutically        acceptable metabolites, and pharmaceutically acceptable salts        thereof.

More preferably, in Formula III(a): R¹ is a substituted or unsubstitutedbicyclic heteroaryl, or a group of the formula CH═CH—R³ where R³ is asubstituted or unsubstituted aryl or heteroaryl; Y is O, S, C═CH₂, C═O,NH, or N-(C₁-C₈ alkyl); and R⁸ is a substituted or unsubstituted aryl orheteroaryl.

In another preferred general embodiment, compounds of the invention areof Formula IV:

wherein:

-   -   R¹ is a substituted or unsubstituted aryl or heteroaryl, or a        group of the formula CH═CH—R³ or CH═N—R³, where R³ is a        substituted or unsubstituted alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl;    -   Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, or N—(C₁-C₈        alkyl);    -   R⁹ is a substituted or unsubstituted alkyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl,        cycloalkoxyl, NH-(C₁-C₈ alkyl), NH-(aryl), NH-(heteroaryl),        N═CH-(alkyl), NH(C═O)R¹¹, or NH₂, where R¹¹ is independently        selected from hydrogen, substituted or unsubstituted alkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and    -   R¹⁰ is independently selected from hydrogen, halogen, and        lower-alkyl;        and pharmaceutically acceptable prodrugs, pharmaceutically        acceptable metabolites, and pharmaceutically acceptable salts        thereof.

More preferably, in Formula IV: R¹ is a group of the formula CH═CH—R³where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is S orNH, and R⁹ is a substituted or unsubstituted alkyl, alkoxyl, orNH-(heteroaryl).

Most preferred are compounds of the invention selected from:

The invention also relates to a method of modulating and/or inhibitingthe kinase activity of VEGF-R, FGF-R, a CDK complex, CHK1, LCK, TEK,FAK, and/or phosphorylase kinase by administering a compound of theFormula I, II, III, or IV, or a pharmaceutically acceptable prodrug,pharmaceutically active metabolite, or pharmaceutically acceptable saltthereof. Preferred compounds of the present invention that haveselective kinase activity-i.e., they possess significant activityagainst one or more specific kinases while possessing less or minimalactivity against one or more different kinases. In one preferredembodiment of the invention, compounds of the present invention arethose of Formula I possessing substantially higher potency against VEGFreceptor tyrosine kinase than against FGF-R1 receptor tyrosine kinase.The invention is also directed to methods of modulating VEGF receptortyrosine kinase activity without significantly modulating FGF receptortyrosine kinase activity.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. For example, compounds of Formula I, II,III, or IV which possess antiangiogenic activity may be co-administeredwith cytotoxic chemotherapeutic agents, such as taxol, taxotere,vinblastine, cis-platin, doxorubicin, adriamycin, and the like, toproduce an enhanced antitumor effect. Additive or synergisticenhancement of therapeutic effect may also be obtained byco-administration of compounds of Formula I, II, m, or IV which possessantiangiogenic activity with other antiangiogenic agents, such ascombretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib,EMD121974, IM862, anti-VEGF monoclonal antibodies, and anti-KDRmonoclonal antibodies.

The invention also relates pharmaceutical compositions, each comprisingan effective amount of an agent selected from compounds of Formula I andpharmaceutically acceptable salts, pharmaceutically active metabolites,and pharmaceutically acceptable prodrugs thereof; and a pharmaceuticallyacceptable carrier or vehicle for such agent. The invention furtherprovides methods of treating cancer as well as other disease statesassociated with unwanted angiogenesis and/or cellular proliferation,comprising administering effective amounts of such an agent to a patientin need of such treatment.

DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS

The inventive compounds of the Formula I, II, III, and IV are useful formediating the activity of protein kinases. More particularly, thecompounds are useful as anti-angiogenesis agents and as agents formodulating and/or inhibiting the activity of protein kinases, thusproviding treatments for cancer or other diseases associated withcellular proliferation mediated by protein kinases.

The term “alkyl” as used herein refers to straight- and branched-chainalkyl groups having one to twelve carbon atoms. Exemplary alkyl groupsinclude methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and the like. The term “lower alkyl” designates an alkylhaving from 1 to 8 carbon atoms (a C₁₋₄-alkyl). Suitable substitutedalkyls include fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, and the like.

The term “alkylidene” refers to a divalent radical having one to twelvecarbon atoms. Illustrative alkylidene groups include CH₂, CHCH₃, (CH₃)₂,and the like.

The term “alkenyl” refers to straight- and branched-chain alkenyl groupshaving from two to twelve carbon atoms. Illustrative alkenyl groupsinclude prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl,hex-2-enyl, and the like.

The term “alkynyl” refers to straight- and branched-chain alkynyl groupshaving from two to twelve carbon atoms.

The term “cycloalkyl” refers to saturated or partially unsaturatedcarbocycles having from three to twelve carbon atoms, including bicyclicand tricyclic cycloalkyl structures. Suitable cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

A “heterocycloalkyl” group is intended to mean a saturated or partiallyunsaturated monocyclic radical containing carbon atoms, preferably 4 or5 ring carbon atoms, and at least one heteroatom selected from nitrogen,oxygen and sulfur.

The terms “aryl” and “heteroaryl” refer to monocyclic and polycyclicunsaturated or aromatic ring structures, with “aryl” referring to thosethat are carbocycles and “heteroaryl” referring to those that areheterocycles. Examples of aromatic ring structures include phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl,pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl,1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl(thianaphthenyl), and the like. Such moieties may be optionallysubstituted by a fused-ring structure or bridge, for example OCH₂—O.

The term “alkoxy” is intended to mean the radical —O-alkyl. Illustrativeexamples include methoxy, ethoxy, propoxy, and the like.

The term “aryloxy” respresents —O-aryl, wherein aryl is defined above.

The term “cycloalkoxyl” represents —O-cycloalkyl, wherein cycloalkyl isdefined above.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

In general, the various moieties or functional groups for variables inthe formulae may be optionally substituted by one or more suitablesubstituents. Exemplary substituents include a halogen (F, Cl, Br, orI), lower alkyl, —OH, —NO₂, —CN, —CO₂H, —O-lower alkyl, -aryl,-aryl-lower alkyl, —CO₂CH₃, —CONH₂, —OCH₂CONH₂, —NH₂, —SO₂NH₂, haloalkyl(e.g., —CF₃, —CH₂CF₃), —O-haloalkyl (e.g., —OCF₃, —OCHF₂), and the like.

The terms “comprising” and “including” are used in an open, non-limitingsense.

It is understood that while a compound of Formula I may exhibit thephenomenon of tautomerism, the formula drawings within thisspecification expressly depict only one of the possible tautomericforms. It is therefore to be understood that within the invention theformulae are intended to represent any tautomeric form of the depictedcompound and is not to be limited merely to a specific tautomeric formdepicted by the formula drawings.

Some of the inventive compounds may exist as single stereoisomers (i.e.,essentially free of other stereoisomers), racemates, and/or mixtures ofenantiomers and/or diastereomers. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Preferably, the inventive compounds that areoptically active are used in optically pure form.

As generally understood by those skilled in the art, an optically purecompound having one chiral center is one that consists essentially ofone of the two possible enantiomers (i.e., is enantiomerically pure),and an optically pure compound having more than one chiral center is onethat is both diastereomerically pure and enantiomerically pure.Preferably, the compounds of the present invention are used in a formthat is at least 90% optically pure, that is, a form that contains atleast 90% of a single isomer (80% enantiomeric excess (“e.e.”) ordiastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e.or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), andmost preferably at least 99% (98% e.e. or d.e.).

Additionally, the formulas are intended to cover solvated as well asunsolvated forms of the identified structures. For example, Formula Iincludes compounds of the indicated structure in both hydrated andnon-hydrated forms. Other examples of solvates include the structures incombination with isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, or ethanolamine.

In addition to compounds of the Formula I, II, III, and IV, theinvention includes pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of such compounds.

“A pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound.

“A pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound or salt thereof. Metabolites of a compound maybe identified using routine techniques known in the art and theiractivities determined using tests such as those described herein.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art See, e.g., Bertolini, G. et al., J.Med. Chem., 40, 2011-2016 (1997); Shan, D. et al., J. Pharm. Sci., 86(7), 765-767; Bagshawe K., Drug Dev. Res., 34, 220-230 (1995); Bodor,N., Advances in Drug Res., 13, 224-331 (1984); Bundgaard, H., Design ofProdrugs (Elsevier Press 1985); and Larsen, I. K., Design andApplication of Prodrugs, Drug Design and Development (Krogsgaard-Larsenet al., eds., Harwood Academic Publishers, 1991).

“A pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of thespecified compound and that is not biologically or otherwiseundesirable. A compound of the invention may possess a sufficientlyacidic, a sufficiently basic, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases, and inorganicand organic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds and salts may exist in differentcrystal or polymorphic forms, all of which are intended to be within thescope of the present invention and specified formulas.

Therapeutically effective amounts of the agents of the invention may beused to treat diseases mediated by modulation or regulation of proteinkinases. An “effective amount” is intended to mean that amount of anagent that, when administered to a mammal in need of such treatment, issufficient to effect treatment for a disease mediated by the activity ofone or more protein kinases, such as tryosine kinases. Thus, e.g., atherapeutically effective amount of a compound of the Formula I, salt,active metabolite or prodrug thereof is a quantity sufficient tomodulate, regulate, or inhibit the activity of one or more proteinkinases such that a disease condition which is mediated by that activityis reduced or alleviated.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the mammal inneed of treatment, but can nevertheless be routinely determined by oneskilled in the art. “Treating” is intended to mean at least themitigation of a disease condition in a mammal, such as a human, that isaffected, at least in part, by the activity of one or more proteinkinases, such as tyrosine kinases, and includes: preventing the diseasecondition from occurring in a mammal, particularly when the mammal isfound to be predisposed to having the disease condition but has not yetbeen diagnosed as having it; modulating and/or inhibiting the diseasecondition; and/or alleviating the disease condition.

The inventive agents may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available.

In one general synthetic process, compounds of Formula I are preparedaccording to the following reaction scheme:

6-Nitroindazole (compound V) is treated with iodine and base, e.g.,NaOH, in an aqueous/organic mixture, preferably with dioxane. Themixture is acidified and the product isolated by filtration. To theresulting 3-iodo-6-nitroindazole in dichloromethane-50% aqueous KOH at0° C. is added a protecting group (“Pg”) reagent (wherein X=halo),preferably trimethylsilylethoxymethyl chloride (SEM-Cl), and a phasetransfer catalyst, e.g., tetrabutylammonium bromide (TBABr). After 1-4hours, the two phases are diluted, the organics are separated, driedwith sodium sulfate, filtered and concentrated. The crude product ispurified by silica gel chromatography to give compounds of formula VI.Treatment of compounds of formula VI in a suitable organic solvent witha suitable R¹-organometallic reagent, preferably an R¹-boronic acid, inthe presence of aqueous base, e.g., sodium carbonate, and a suitablecatalyst, preferably Pd(PPh₃)₄ gives, after extractive work-up andsilica gel chromatography, compounds of formula VII. The R¹ substituentmay be exchanged within compounds of formula VII or later intermediatesthroughout this scheme by oxidative cleavage (e.g., ozonolysis) followedby additions to the resulting aldehyde functionality with Wittig orcondensation transformations (typified in Example 42(a-e)). Treatment ofcompounds of formula VII with a reducing agent, preferably SnCl₂,provides, after conventional aqueous work up and purification, compoundsof formula VIII. For the series of derivatives where Y═NH or N-loweralkyl, compounds of formula VIII may be treated with aryl or heteroarylchlorides, bromides, iodides or triflates in the presence of a base,preferably Cs₂CO₃, and catalyst, preferably Pd-BINAP, (and where YN-lower alkyl, with a subsequent alkylation step) to provide compoundsof formula X. To produce other Y linkages, sodium nitrite is added tocompounds of formula VIII under chilled standard aqueous acidicconditions followed by the addition of potassium iodide and gentlewarming. Standard work-up and purification produces iodide compounds offormula IX.

Treatment of compounds of formula Ex with an organometallic reagent,e.g., butyllithium, promotes lithium halogen exchange. This intermediateis then reacted with an R² electrophile, e.g., a carbonyl or triflate,through the possible mediation of additional metals and catalysts,preferably zinc chloride and Pd(PPh₃)₄ to provide compounds of formulaX. Alternatively, compounds of formula IX may be treated with anorganometallic reagent such as an organoboronic acid in the presence ofa catalyst, e.g., Pd(PPh₃)₄, under a carbon monoxide atmosphere to givecompounds of formula X. Alternatively, for derivatives where Y═NH or S,compounds of formula IX may be treated with appropriate amines or thiolsin the presence of base, preferably Cs₂CO₃ or K₃PO₄ and a catalyst,preferably Pd-BINAP or Pd-(bis-cyclohexyl)biphenylphosphine to providecompounds of formula X. Conventional functional group interchanges, suchas oxidations, reductions, alkylations, acylations, condensations, anddeprotections may then be employed to further derivatize this seriesgiving final compounds of Formula I.

The inventive compounds of Formula I may also be prepared accordinggeneral procedure shown in the following scheme:

6-Iodoindazole (XI) is treated with iodine and base, e.g., NaOH, in anaqueous/organic mixture, preferably with dioxane. The mixture isacidified and the product XII is isolated by filtration. To theresulting 3,6 di-iodoindazole in dichloromethane-50% aqueous KOH at 0°C. is added a protecting group reagent, preferably SEM-Cl, and a phasetransfer catalyst, e.g., TBABr. The two phases are diluted, the organicsseparated, dried with sodium sulfate, filtered and concentrated. Thecrude product is purified by silica gel chromatography to give compoundsof the formula XIII. Treatment of compounds of formula XIII in asuitable organic solvent with a suitable R²-organometallic reagent,e.g., R²-ZnCl or boron R²-boron reagent and a suitable catalyst,preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gelchromatography, compounds of formula XIV. Treatment of compounds offormula XIV in a suitable organic solvent with a suitableR¹-organometallic reagent (e.g., boron R¹-boron reagent or R¹-ZnCl), inthe presence of aqueous base, sodium carbonate, and a suitable catalyst,preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gelchromatography, compounds of formula XV. Conventional functional groupinterchanges, such as oxidations, reductions, alkylations, acylations,condensations and deprotections may then be employed to furtherderivatize this series giving final compounds of Formula I.

Alternatively, compounds of Formula I where R² is a substituted orunsubstituted Y—Ar, where Y is O or S may be prepared according to thefollowing general scheme:

A stirred acetone solution of 3-chloro-cyclohex-2-enone (XV), H—R², andanhydrous potassium carbonate is refluxed for 15-24 hours, cooled, andfiltered. Concentrating and chromatographing the filtrate on silica gelgives 3-R²-cyclohex-2-enone (XVI).

The ketones of formula XVI may be reacted with a suitable base (M-B),preferably lithium bis(trimethylsily)amide, and reacted with R¹—CO—X(where X=halogen), which after standard acid work up and purificationprovides compounds of the formula XVII. This product, in HOAc/EtOH,combined with hydrazine monohydrate, is heated at a suitable temperaturefor an appropriate time period, preferably at 60-80° C. for 24 hours.After cooling, the mixture is poured into saturated sodium bicarbonatesolution, extracted with an organic solvent, concentrated, and purifiedon silica gel to give compounds of formula XVIII. Compounds of formulaXVIII may be oxidized using a variety of known methods to give compoundsof the Formula I.

Other compounds of Formula I may be prepared in manners analogous to thegeneral procedures described above or the detailed procedures describedin the examples herein. The affinity of the compounds of the inventionfor a receptor may be enhanced by providing multiple copies of theligand in close proximity, preferably using a scaffolding provided by acarrier moiety. It has been shown that provision of such multiplevalence compounds with optimal spacing between the moieties dramaticallyimproves binding to a receptor. See, e.g, Lee et al., Biochem, 23, 4255(1984). The multivalency and spacing can be controlled by selection of asuitable carrier moiety or linker units. Such moieties include molecularsupports which contain a multiplicity of functional groups that can bereacted with functional groups associated with the compounds of theinvention. Of course, a variety of carriers can be used, includingproteins such as BSA or HAS, a multiplicity of peptides including, forexample, pentapeptides, decapeptides, pentadecapeptides, and the like.The peptides or proteins can contain the desired number of amino acidresidues having free amino groups in their side chains; however, otherfunctional groups, such as sulfhydryl groups or hydroxyl groups, canalso be used to obtain stable linkages.

Compounds that potently regulate, modulate, or inhibit the proteinkinase activity associated with receptors VEGF, FGF, CDK complexes, TEK,CHK1, LCK, FAK, and phosphorylase kinase among others, and which inhibitangiogenesis and/or cellular profileration is desirable and is onepreferred embodiment of the present invention. The present invention isfurther directed to methods of modulating or inhibiting protein kinaseactivity, for example in mammalian tissue, by administering an inventiveagent. The activity of the inventive compounds as modulators of proteinkinase activity, such as the activity of kinases, may be measured by anyof the methods available to those skilled in the art, including in vivoand/or in vitro assays. Examples of suitable assays for activitymeasurements include those described in Parast C. et al., BioChemistry,37, 16788-16801(1998); Jeffrey et al., Nature, 376, 313-320 (1995); WIPOInternational Publication No. WO 97/34876; and WIPO InternationalPublication No. WO 96/14843. These properties may be assessed, forexample, by using one or more of the biological testing procedures setout in the examples below.

The active agents of the invention may be formulated into pharmaceuticalcompositions as described below. Pharmaceutical compositions of thisinvention comprise an effective modulating, regulating, or inhibitingamount of a compound of Formula I, II, III, or IV and an inert,pharmaceutically acceptable carrier or diluent. In one embodiment of thepharmaceutical compositions, efficacious levels of the inventive agentsare provided so as to provide therapeutic benefits involving modulationof protein kinases. By “efficacious levels” is meant levels in which theeffects of protein kinases are, at a minimum, regulated. Thesecompositions are prepared in unit-dosage form appropriate for the modeof administration, e.g., parenteral or oral administration.

An inventive agent is administered in conventional dosage form preparedby combining a therapeutically effective amount of an agent (e.g., acompound of Formula I) as an active ingredient with appropriatepharmaceutical carriers or diluents according to conventionalprocedures. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

The pharmaceutical carrier employed may be either a solid or liquid.Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryof liquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the carrier or diluent may include time-delay or time-releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

A variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation will be in the form of syrup, emulsion, soft gelatincapsule, sterile injectable solution or suspension in an ampoule or vialor non-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of an inventive agent is dissolved in an aqueoussolution of an organic or inorganic acid, such as 0.3M solution ofsuccinic acid or citric acid. If a soluble salt form is not available,the agent may be dissolved in a suitable cosolvent or combinations ofcosolvents. Examples of suitable cosolvents include, but are not limitedto, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the totalvolume. In an exemplary embodiment, a compound of Formula I is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

It will be appreciated that the actual dosages of the agents used in thecompositions of this invention will vary according to the particularcomplex being used, the particular composition formulated, the mode ofadministration and the particular site, host and disease being treated.Optimal dosages for a given set of conditions can be ascertained bythose skilled in the art using conventional dosage-determination testsin view of the experimental data for an agent. For oral administration,an exemplary daily dose generally employed is from about 0.001 to about1000 mg/kg of body weight, more preferably from about 0.001 to about 50mg/kg body weight, with courses of treatment repeated at appropriateintervals. Administration of prodrugs are typically dosed at weightlevels which are chemically equivalent to the weight levels of the fullyactive form.

The compositions of the invention may be manufactured in mannersgenerally known for preparing pharmaceutical compositions, e.g., usingconventional techniques such as mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen.For injection, the agents of the invention may be formulated intoaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carriersknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, dragees, capsules, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained using a solid excipient in admixture with the active ingredient(agent), optionally grinding the resulting mixture, and processing themixture of granules after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include: fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol; andcellulose preparations, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, odium carboxymethylcellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention are conveniently delivered in theform of an aerosol pray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

For administration to the eye, a compound of the Formula I, II, III, orIV is delivered in a pharmaceutically acceptable ophthalmic vehicle suchthat the compound is maintained in contact with the ocular surface for asufficient time period to allow the compound to penetrate the cornealand internal regions of the eye, including, for example, the anteriorchamber, posterior chamber, vitreous body, aqueous humor, vitreoushumor, cornea, iris/cilary, lens, choroid/retina and selera. Thepharmaceutically acceptable ophthalmic vehicle may be an ointment,vegetable oil, or an encapsulating material. A compound of the inventionmay also be injected directly into the vitreous and aqueous humor.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g, containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may alsobe formulated as a depot preparation. Such long-acting formulations maybe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) orion-exchange resins, or as sparingly soluble derivatives, for example,as a sparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds is a cosolvent systemcomprising benzyl alcohol, a nonpolar surfactant, a water-miscibleorganic polymer, and an aqueous phase. The cosolvent system may be a VPDcosolvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution.This co-solvent system dissolves hydrophobic compounds well, and itselfproduces low toxicity upon systemic administration. Naturally, theproportions of a co-solvent system may be varied considerably withoutdestroying its solubility and toxicity characteristics. Furthermore, theidentity of the co-solvent components may be varied: for example, otherlow-toxicity nonpolar surfactants may be used instead of polysorbate 80;the fraction size of polyethylene glycol may be varied; otherbiocompatible polymers may replace polyethylene glycol, e.g. polyvinylpyrrolidone; and other sugars or polysaccharides may be substituted fordextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are knownby those skilled in the art. Sustained-release capsules may, dependingon their chemical nature, release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Some of the compounds of the invention may be provided as salts withpharmaceutically compatible counter ions. Pharmaceutically compatiblesalts may be formed with many acids, including hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree-base forms.

The preparation of preferred compounds of the present invention isdescribed in detail in the following examples, but the artisan willrecognize that the chemical reactions described may be readily adaptedto prepare a number of other protein kinase inhibitors of the invention.For example, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by changing to other suitable reagents known in the art, or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

EXAMPLES

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd.and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane,toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received. All solvents were purified using standard methodsreadily known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally under a positivepressure of argon or nitrogen or with a drying tube, at ambienttemperature (unless otherwise stated), in anhydrous solvents, and thereaction flasks were fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Analytical thin layer chromatography (TLC) was performed onglass-backed silica gel 60 F. 254 plates Analtech (0.25 mm) and elutedwith the appropriate solvent ratios (v/v), and are denoted whereappropriate. The reactions were assayed by TLC and terminated as judgedby the consumption of starting material.

Visualization of the TLC plates was done with a p-anisaldehyde sprayreagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt % inethanol) and activated with heal Work-ups were typically done bydoubling the reaction volume with the reaction solvent or extractionsolvent and then washing with the indicated aqueous solutions using 25%by volume of the extraction volume unless otherwise indicated. Productsolutions were dried over anhydrous Na₂SO₄ prior to filtration andevaporation of the solvents under reduced pressure on a rotaryevaporator and noted as solvents removed in vacuo. Flash columnchromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was doneusing Baker grade flash silica gel (47-61 μm) and a silica gel: crudematerial ratio of about 20:1 to 50:1 unless otherwise stated.Hydrogenolysis was done at the pressure indicated in the examples or atambient pressure.

¹H-NMR spectra were recorded on a Bruker instrument operating at 300 MHzand “³C-NMR spectra were recorded operating at 75 MHz. NMR spectra wereobtained as CDCl₃ solutions (reported in ppm), using chloroform as thereference standard (7.25 ppm and 77.00 ppm) or CD₃OD (3.4 and 4.8 ppmand 49.3 ppm), or internally tetramethylsilane (0.00 ppm) whenappropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometeras neat oils, as KBr pellets, or as CDCl₃ solutions, and when given arereported in wave numbers (cm⁻¹). The mass spectra were obtained usingLSIMS or electrospray. All melting points (mp) are uncorrected.

Example 1(a)3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

The3-[E/Z-2-(3,4-dimethoxy-phenyl)vinyl]-6-[3-methoxy-4-(methoxymethoxy)phenyl]-1H-indazole(−205 mg, 0.461 mmol (theoretical)) was dissolved in tetrahydrofuran(THF, 10 mL) and was treated with water (10 mL) and trifluoroacetic acid(TFA, 20 mL). The reaction mixture was allowed to stir at 23° C. for 30minutes (min.). The mixture was diluted with toluene (100 μl) and thevolatile materials were removed under reduced pressure (30 mm Hg, 35°C.) to give a concentrated volume of −5 mL. Again, toluene (100 mL) wasadded and the mixture was concentrated under reduced pressure to givecrude material which still contained some acid. The material waspartitioned between ethyl acetate and saturated sodium bicarbonate, theorganic material was separated, dried over sodium sulfate, decanted, andconcentrated under reduced pressure. The residue, a mixture of olefinisomers, (−185 mg, 0.461 mmol (theoretical)) was taken up indichloromethane (50 mL) at 23° C. and was treated with iodine (80 mg).The mixture was allowed to stir at 23° C. for 12 hours (h). The mixturewas treated with saturated sodium bicarbonate (10 mL) and 5% aqueoussodium bisulfite (10 mL). The mixture was diluted with ethyl acetate(200 mL) and the organic material was washed with saturated sodiumbicarbonate (100 mL), dried over sodium sulfate, decanted, andconcentrated under reduced pressure to give crude product. The crude waspurified on silica (40 mL, 6:4->7:3 ethyl acetate/hexane) and allfractions containing desired were combined, concentrated andprecipitated from a dichloromethane/hexane bilayer (1:3) to give3-E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxyhydroxy-phenyl)-1H-indazole as a white solid (93 mg combined crops):R_(f) sm 0.42, p 0.35 (ethyl acetate-hexane 7:3); FTIR (thin film) 3324,1600, 1514, 1463, 1422, 1264, 1137, 1024, 959, 852 cm⁻¹; ¹H NMR (CDCl₃)δ 10.0 (s, 1H), 8.08 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.49 (d, 1H,J=16.6 Hz), 7.45 (dd, 1H, J=1.4, 8.4 Hz), 7.34 (d, 1H, J=16.6 Hz),7.20-7.12 (m, 4H), 7.03 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.2 Hz), 5.68(bs, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H); ¹³C NMR (CDCl₃) δ149.6, 149.5, 146.0, 144.0, 142.6, 140.8, 133.9, 131.4, 130.7, 121.7,121.4, 120.9, 120.4, 120.2, 118.6, 115.4, 111.7, 110.8, 109.1, 108.2,56.4, 56.3, 56.2. HRMS (ES) [m+H]/z Calc'd 403.1658, found 403.1658.[m−H]/z Calc'd 401. Found 401.

The starting material was prepared as follows:

To 6-aminoindazole (40.8 g. 0.3065 mol, 1 equiv) in a 2-liter (2-L)round-bottom flask containing a large magnetic stir bar was added ice(256 g), followed by water (128 mL) and the reaction vessel was loweredinto an ice bath. To this stirring slurry at 0° C. was addedconcentrated aqueous HCl (128 mL, 1.53 mol, 5 equiv). Immediately after,a solution of NaNO₂ (23.3 g, 0.338 mol, 1.1 equiv) in water (96 mL) wasadded. After 10 min of stirring at 0° C., KI (61 g, 0.368 mol, 1.2equiv) was added very slowly at first (−100 mg at a time because thefirst small bits of KI cause an abrupt evolution of gas) then morerapidly (5 min total time). The cold bath was removed and the reactionmixture was warmed to 40° C. (gas evolved). When the rate of gasevolution decreased (−30 min) the reaction mixture was warmed to 50° C.for 30 min. The mix was then cooled to 23° C., and 3N NaOH (320 mL) wasadded to neutralize followed by 50% saturated NaHCO₃ (320 mL). Theslurry was then filtered through a Buchner funnel to give a darkreddish-brown solid. The solid was taken up in warm THF (800 mL) andsilica (600 mL dry) was added with stirring. To this slurry was addedhexane (1.2 L) and the mix was vacuum filtered through a pad of silica(300 mL) in a large fritted filter. The silica was further washed with 2L of 40% THF in hexane. The filtrates were combined and concentratedunder reduced pressure to give a solid. The solid was further trituratedwith ethyl acetate (˜100 mL), filtered and dried under reduced pressureto give 6-iodo-1H-indazole as a light brown solid (36.1 g, 48% yield):R_(f) sm 0.12, p 0.48 (Hex-EtOAc 1:1); ¹H NMR (300 MHz, CDCl₃) 7.9 (s,1H), 7.8 (s, 1H), 7.42 (d, 1H), 7.33 (d, 1H); MS (ES) [m+H]/z Calc'd245, Found 245, [m−H]/z Calc'd 243, Found 243.

To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF(100 mL) cooled to 0° C. under argon, was added sodium t-butoxide (2.89g, 30.1 mmol, 1 equiv). A color change from orange to red was observed.Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added inone portion and the ice bath was removed allowing the reaction mixtureto warm to 23° C. After 40 min the mixture was quenched with saturatedammonium chloride and partitioned between water and ethyl acetate. Theaqueous was extracted a total of 3 times with ethyl acetate. Thecombined organic material was washed with brine, dried over sodiumsulfate and concentrated under reduced pressure to give6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orangesolid (12.8 g, 100% yield, 2:1 mixture). ¹H NMR (CDCl₃) 8.51 (s, 1H),7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d,0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz),7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).

A mixture of 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(5.78 g, 13.56 mmol, 1.00 equiv) and3-methoxy-4-(methoxymethoxy)benzene-boronic acid (3.45 g, 16.27 mmol,1.20 equiv) under argon was dissolved in dioxane (15 mL) and water (2.0mL). To this solution was added triethylamine (2.83 mL, 20.3 mmol, 1.5equiv), potassium carbonate (2.8 g. 20.3 mmol, 1.5 equiv) anddichlorobis(triphenylphosphine)palladium (476 mg, 0.678 mmol, 0.05equiv). The reaction mixture was heated to 90° C. for 2 h and then wascooled to 23° C. The mixture was separated between ethyl acetate (250mL) and saturated sodium bicarbonate (150 mL). The organic material wasdried over sodium sulfate, decanted and concentrated under reducedpressure to give crude6-(3-methoxy-4-methoxymethoxy-phenyl)1-(2,4,6-triethyl-benzenesulfonyl)-1H-indazolethat was dried under high vacuum for 15 h and was used without furtherpurification.

3-Methoxy-4-(methoxymethoxy)benzeneboronic acid was prepared as follows:In a 100 mL flask a mixture of 50% KOH in water (20 g KOH, 7 equiv, 20 gice) was prepared under argon. To this rapidly stirring mixture at 0° C.(maintained with an ice bath) was added dichloromethane (50 mL) followedby 4-bromo-2-methoxyphenol (10.1 g, 50 mmol, 1.00 equiv),methoxymethylchloride (MOMCl) (4.00 mL, 42.5 mmol, 1.05 equiv) andtetrabutylammonium bromide (322 mg, 1 mmol, 0.02 equiv). The bath wasremoved and the mixture was slowly allowed to warm to 23° C. with rapidstirring for 2 h. The mixture is transferred to a separatory funnel anddiluted with dichloromethane (350 mL) and water (300 mL) which are usedto aid the transfer. The organic material (now the bottom layer) areseparated, dried over sodium sulfate, decanted and concentrated underreduced pressure to give 4-bromo-2-methoxy-1-(methoxymethoxy)benzene asa yellow liquid which is pure by ¹H NMR (11.9 g, 97%): ¹H NMR (CDCl₃) δ7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI) [m+H]/zCalc'd 235, found 235. In a 50 mL round-bottom flask,4-bromo-2-methoxy-1-(methoxymethoxy)benzene (4.80 g, 19.4 mmol, 1.00equiv) was taken up in THF (35 mL) and was cooled to −78° C. (20 min forthis volume). To this was added n-BuLi (12.75 mL, 1.6 M in hexane, 20.4mmol. 1.05 equiv) and the mixture was allowed to stir at −78° C. for 40min. This was then added via cannula to a second flask containingB(OMe)₃ (22 mL, 194 mmol, 10 equiv) in THF (50 mL) at −78° C. After 20min, the cold bath was removed. After 15 min of warming (−0° C., ice onthe side of the flask begins to melt) water (50 mL) was added to thereaction mixture which was stirred for 45 min. The mixture wasconcentrated under reduced pressure to remove most THF and was thenpartitioned between ethyl acetate (300 mL) and water (150 mL) which wasmade acidic by addition of a small amount of 20% citric acid (−10 mL).The organic material was dried over sodium sulfate and concentratedunder reduced pressure to give a solid. Trituration with ethyl acetate(10 mL) and hexane (5 mL) followed by filtering gave3-methoxy-4-(methoxymethoxy)benzene-boronic acid as a white solid (3.15g, 77%): R_(f) sm 0.59, p 0.18 (ethyl acetate-hexane 1:1); ¹H NMR(CDCl₃) δ 7.85 (d, 1H, J=8 Hz), 7.72 (s, 1H), 7.22 (d, 1H, J=8 Hz), 5.30(s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).

Unpurified6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(under argon) was dissolved in THF (20 mL) and was treated with 1N NaOHin MeOH (70 mL degassed by bubbling through argon for 3 to 5 min). Themixture was heated to 45° C. for 1 h and allowed to cool. The mixturewas neutralized by addition of 1N HCl (50 mL) followed by saturatedsodium bicarbonate (200 mL). The product was extracted into ethylacetate (350 mL), dried over sodium sulfate and concentrated underreduced pressure to give crude6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole. Purification bysilica gel chromatography (500 mL silica, 20% ethyl acetate in benzene(1.8 L), 30% ethyl acetate in benzene (1.8 L)) gave6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 31%): ¹H NMR(CDCl₃) δ 7.80 (s, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.52 (s, 1H), 7.29 (d,1H, J=8.5 Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES)[m+Na]/z Calc'd 337, found 337; [m+H]/z Calc'd 349, found 349.

In a 100-mL round-bottom flask under argon,6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 4.18 mmol, 1equiv) was dissolved in dioxane (25 mL) and 3N NaOH (14 mL). Thismixture was treated with iodine (1.17 g, 14.60 mmol, 1.10 equiv) addedin ˜5 portions (˜10 min). Several (−4) additional portions of iodine (50mg each) were added until the reaction was complete as visualized by TLC(3:7 ethyl acetate/hexane). The mixture was acidified with 20% citricacid (25 mL) and 5% NaHSO3 (20 mL) was added. The mixture waspartitioned between ethyl acetate (150 mL) and water (100 mL). Theorganic material was washed with saturated sodium bicarbonate (80 mL)and brine (50 mL) and were dried over sodium sulfate and concentratedunder reduced pressure. Purification by crystallization from ethylacetate (3 mL) then hexane (7 mL) gave pure3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole as a solid(1.33 g, 78%): ¹H NMR (CDCl₃) δ 10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d,1H, J=8.5 Hz), 7.47 (dd, 1H, J=1.3, 8.5 Hz), 7.18 (m, 3H), 5.29 (s, 2H),3.99 (s, 3H), 3.55 (s, 3H).

In a 100 mL round-bottom flask,3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (921 mg, 2.245mmol, 1.00 equiv) was dissolved in THF (36 mL) and cooled to −78° C.(allow 8 min at this scale). A solution of PhLi (25 mL 1.8 M, 4.49 mmol,2.00 equiv) was added and the mixture was allowed to stir for 30 min. Asolution of s-BuLi (3.63 mL, 4.71 mmol, 2.1 equiv) was added and thereaction mixture was allowed to stir for 1 h at −78° C. Neat DMF (1.4mL, 18 mmol, 8.0 equiv) was added. The cold bath was removed and thereaction was allowed to slowly warm to 0° C. in the air. As the icemelted saturated sodium bicarbonate (20 mL) was added. The product wasextracted into ethyl acetate (200 mL) from saturated sodium bicarbonate(75 mL more), dried over sodium sulfate, decanted and concentrated underreduced pressure. Purification by silica gel chromatography (450 mLsilica, 4:6 ethyl acetate/hexane) gave6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (498mg, 71%)): R_(f) sm 0.30, p 0.14 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.67(s, 1H), 7.60 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.7 Hz), 7.19 (m, 2H),5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (441mg, 1.41 mmol, 1.0 equiv) was taken up as a suspension indichloromethane (15 mL) and was cooled to 0° C. This mixture was treatedwith mesitylene sulfonyl chloride (324 mg, 1.48 mmol, 1.05 equiv) anddimethylamino pyridine (DMAP) (181 mg, 1.48 mmol, 1.05 equiv). Themixture was allowed to stir for 1 h at 0° C. and was quenched with theaddition of water. The mixture was partitioned between water and a 1:1ethyl acetate/hexane organic layer. The organic material was dried oversodium sulfate, decanted and concentrated under reduced pressure to givecrude material which was purified by silica gel chromatography (50 mLsilica, 3:7 ethyl acetate/hexane) to give6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde(374 mg, 54%): R_(f) sm 0.17, p 0.53 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.73 (dd,1H, J=1.4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H), 4.08 (s,3H), 3.71 (s, 3H), 2.74 (s, 6H), 2.40 (s, 3H).

Finely ground triphenyl(3,4-dimthoxybenzyl)phosphonium bromide (1.09 g,2.22 mmol, 4.0 equiv) was taken up as a slurry in THF (15 mL) and wascooled to −78° C. To this mixture was added n-BuLi (1.04 mL, 1.6 M, 1.66mmol, 3.0 equiv) which gave a red/orange solution. The mixture wasallowed to warm to 23° C. for 1 h. This mixture was then added to a 0°C. solution of6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde(274 mg, 0.554 mmol, 1.0 equiv) in THF (5 mL) via cannula. The resultingmixture was allowed to stir at 0° C. for 10 min and was quenched withsaturated sodium bicarbonate. The resulting mixture was partitionedbetween saturated sodium bicarbonate and ethyl acetate. The organicmaterial was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (50 mL silica. 3:7->4:6 ethylacetate/hexane) to give a 2.5:1 mixture of cis/trans3-[2-(3,4-dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(289 mg, 83%): R_(f) sm 0.53, p 0.32 (ethyl acetate-hexane 4:6); ¹H NMR(CDCl₃) δ 8.35 (s, 0.3H), 8.32 (s, 0.7H), 8.03 (d, 0.3H, J=8.4 Hz),7.60-6.85 (m, H), 6.65 (d, 0.7H, J=8.4 Hz), 6.60 (d, 0.7H, J=12.5 Hz),5.30 (s, 0.6H), 5.29 (s, 1.4H), 4.00-3.50 (8 singlets, 12H), 2.72 (s,1.8H), 2.67 (s. 4.2H), 2.34 (s, 3H); MS (ES) [m+H]/z Calc'd 629, found629, [m−H]/z Calc'd 627, found 627.

A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mL total)was prepared under argon and was degassed by vacuum/purge cycles withargon (5 times). In a separate flask,3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(289 mg, 0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon.To this solution was added the above 1M KOH solution (10 mL, 1:1water/MeOH). The reaction was warmed to 30° C. and was allowed to stirfor 7 h. The reaction mix was neutralized by the addition of 20% citricacid (7 mL). The resulting mix was partitioned between ethyl acetate(150 mL) and water (100 mL). The organic material was separated, driedover sodium sulfate, decanted, and concentrated under reduced pressureto give cis and trans3-[2-(3,4-dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)1H-indazole (used crude): R_(f) sm 0.46, p1 0.17, p2 0.23 (ethylacetate-hexane 1:1); ¹H NMR cis isomer (CDCl₃) δ 7.55 (s, 1H), 7.3-7.1(m, 6H), 7.02 (dd, 1H, J=1.9, 8.3 Hz), 6.85 (d, 1H, J=12.5 Hz), 6.78 (d,1H, J=12.5 Hz), 6.74 (d, 1H, 3=8.3 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.70(s, 3H), 3.43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H)/z Calc'd 447, found447, [m−H]/z Calc'd 445, found 445.

Example 1(b) 3-(E-styryl)-6-(3-benzyloxy-4-hydroxy-phenyl)-1H-indazole

Example 1(b) was prepared in a similar manner to that described forExample 1(a), except that 4-bromo-2-benzyloxy-phenol was used instep(iii) in place of 4-bromo-2-methoxy-phenol. R_(f) sm 0.35, p 0.30(ethyl acetate-hexane 4:6); ¹H NMR (CDCl₃) δ 8.06 (d, 1H, J=8.6 Hz),7.63-7.18 (m, 17H), 7.05 (d, 1H, J=8.2 Hz), 5.19 (s, 2H). MS (CI)[m+H]/z Calc'd 419, found 419, [m−H]/z Calc'd 417, found 417.

Example 1(c)3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-allyloxy-4-hydroxy-phenyl)-1H-indazole

Example 1(c) was prepared in a similar manner to that described forExample 1(a), except that 3-allyloxy4-(methoxymethoxy)benzene-boronicacid was used instead of 3-methoxy 4(methoxymethoxy)benzene-boronic acidin step (iii). MS (ESI) [M+H]/z Calc'd 429, found 429; MS (ESI) [M−H]/zCalc'd 427, found 427.

Example 2(a) 3-(Naphthalen-2-yl)(3-methoxy-4-hydroxy-phenyl)-1H-indazole

6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-H-indazole (25 mg,0.055 mmol) was dissolved in a mixture of ethyl acetate (2 mL), benzene(2 mL) and methanol (2 mL). To this solution was added palladium oncarbon (25 mg, 10% wt) and the reaction vessel was vacuum/purged withhydrogen gas for five cycles. The reaction mixture was allowed to stirfor 3 days (d) at 23° C. and was filtered through a plug of Celite.Concentration and purification by silica gel chromatography afforded3-(Naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole (8 mg,40%): ¹H NMR (CDCl₃) δ 10.3 (bs, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J=8Hz), 7.98 (d, 1H, J=8 Hz), 7.90 (m, 1H), 7.7-6.8 (m, 9H), 3.98 (s, 3H).MS (ES) [m+H]/z Calc'd 367, found 367, [m−H]/z Calc'd 365, found 365.

The starting material was prepared as follows:

2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolved in TH(0.75 mL) and cooled to −78° C. The mixture was treated with n-BuLi (226μL, 2.5 M, 6.0 equiv) and was allowed to stir at −78° C. for 30 min. Themixture was then added to freshly dried ZnCl₂ solid (139 mg, 0.80 mmol,8.5 equiv) via cannula and the resulting mix was allowed to warm to 23°C. (during the addition the yellow color disappears). After 30 min at23° C. the mixture is added to a mixture of6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole(60 mg, 0.094 mmol, 1 equiv) and Pd(PPh₃)₄ (6 mg, 0.005 mmol, 0.05equiv) via cannula The resulting solution was allowed to stir for 16 h.Saturated sodium bicarbonate was added and the mixture was partitionedbetween saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL).The organic material was dried over sodium sulfate, decanted andconcentrated. Purification by silica gel chromatography (1:9-2:8 ethylacetate-hexane) gave6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazoleas a solid (42 mg, 70%): R_(f) sm 0.4, p 0.4 (ethyl acetate-hexane 3:7);¹H NMR (CDCl₃) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J=8 Hz),8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s,3H).

6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazolewas prepared in a similar manner as described in Example 1(a), steps (i)to (v).

6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazolewas converted to6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole asdescribed in Example 1(a), step (ix). R_(f) sm 0.40, p 0.17 (ethylacetate-hexane 3:7); ¹H NMR (CDCl₃) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H),7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J=2.0Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H),3.91 (s, 3H).

Example 2(b) 3-phenyl-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 2(b) was prepared in a similar manner to that described forExample 2(a), except that phenyllithium was used in place of2-napthyllitium generated from 2-bromonaphthylene in step (i). ¹H NMR(300 MHz, CDCl₃) δ 7.87 (d, 1H), 7.83 (d, 2H), 755-7.27 (m, 5H), 7.01(m, 2H), 6.80 (d, 1H), 3.83 (s, 3H). MS (ES) [m+H]/z Calc'd 317, Found317, [m−H]/z Calc'd 315, found 315.

Example 2(c)3-(3,4,5-trimethoxyphenyl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 2(c) was prepared in a similar manner to that described forExample 2(a), except that 3,4,5-trimethoxyphenyl bromide was used instep (i) in place of 2-bromonaphthylene. R_(f) sm 0.67, p 0.38 (ethylacetate-hexane 8:2); ¹H NMR (CDCl₃) δ 7.93 (d, 1H, J=8 Hz), 7.58 (s,1H), 7.39 (d, 1H, J=8 Hz), 7.10 (m, 4H), 6.92 (d, 1H, J=8 Hz), 3.90 (s,9H), 3.85 (s, 3H); MS (ES) [m+H]/z Calc'd 407, Found 407, [m−H]/z Calc'd405, Found 405.

Example 2(d)3-(1H-Indol-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 2(d) was prepared in a similar manner to that described forExample 2(a) above, except that 1-phenylsulfonyl-indazole was used inplace of 2-bromonaphthylene in step (i). R_(f) sm 0.20, p 0.15 (ethylacetate-hexane 4:6); ¹H NMR (CDCl₃) δ 10.0 (bs, 1H), 9.05 (bs, 1H), 8.01(d, 1H, J=8.0 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.49 (s, 1H), 7.37 (d, 1H,J=8 Hz), 7.29 (d, 1H, J=8 Hz), 7.2-7.1 (m, 5H), 6.92 (d, 1H, J=8 Hz),5.63 (bs, 1H); MS (ES) [m+H]/z Calc'd 356, Found 356; [m−H]/z Calc'd354, found 354.

Example 2(e)3-(Benzofuran-2-yl)-6-(3-benzyloxy-4-hydroxy-phenyl)-1H-indazole

Example 2(e) was prepared in a similar manner to that described forExample 2(a) above, except that benzofuran was used in place of2-bromonaphthylene in step (i). ¹H NMR (CDCl₃) δ 8.21 (d, 111, J=8.0Hz), 7.60 (m, 3H), 7.307.10 (m, 12H), 7.01 (d, 1H. J=8 Hz), 5.82 (bs,1H), 5.15 (s, 3H).

Example 3 3-(1H-Indol-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-1H-indazole

3-(1H-Benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazolewas converted to4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol accordingto the procedure described in Example 1(a) (3.5 mg, 28%). HRMS (FAB)[m+H]/z Calc'd 357.1351, Found 357.1349.

The starting material was prepared as follows:

6-(3-Methoxy-4-methoxymethoxy-phenyl)1H-indazole-3-carbaldehyde (fromExample 1(a), step (vi)) (20 mg, 0.064 mmol, 1 equiv) was dissolved indegassed 1:1 MeOH-water (0.7 mL) and was treated with acetic acid (19 μL5 equiv), 1,2-diaminobenzene (8.3 mg, 1.2 equiv) and copper(II) acetate(18 mg, 1.4 equiv) at 23° C. The mixture stirred for 30 min, was dilutedwith ethanol (3 mL) and water (2 mL) and was treated with a bubblingstream of SH₂ for 3 min, which gave a black precipitate. The mixture wasallowed to stir for 12 h. The mixture was filtered and concentrated.Purification by silica gel chromatography (6:4 ethyl acetate-hexane)gave3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazoleas a solid (14 mg, 54%); R_(f) sm 0.39, p 0.24 (ethyl acetate-hexane6:4); ¹H NMR (CDCl₃) δ 8.69 d, 1H, J=8 Hz), 7.70 (bs, 2H), 7.58 (s, 1H),7.53 (d, 1H, J=8 Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s, 3H),3.58 (s, 3H); MS (ES) [m+H]/z Calc'd 401, found 401, [m−H]/z Calc'd 399,found 399.

Example 4(a) N-[3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-benzamide

A solution ofN-[3-(2-benzoyl-3-styrl-1H-indazol-6-yloxy)phenyl]-benzamide (0.09 g,0.17 mmol) in 2 mL of 6N HCl (aqueous) and 3 mL of MeOH was heated at65° C. for about 4 h. The cooled solution was poured cautiously intosaturated sodium bicarbonate solution. The precipitate was filtered,collected and chromatographed on silica gel eluting hexanes/EtOAc (1:1).N-(3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-benzamide was obtained as abeige solid (32 mg, 50%): ¹H NMR (DMSO-d₆) δ 13.50 (s, 1H), 10.32 (s,1H), 8.23 (d, 1H, J=8.7 Hz), 7.92 (d, 2H, J=6.8 Hz), 7.72 (d, 2H, J=7.3Hz), 7.71-7.51 (m, 7H), 7.51-7.47 (m, 3H), 7.30 (t, 1H, J=7.2 Hz), 7.05(s, 1H), 7.01 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=8.2, 2.3 Hz). Anal.Calc. for C₂₈H₂₁N₃O₂.0.3H₂O: C, 76.97; H, 4.98: N, 9.62. Found: C,76.94; H, 5.13; N, 9.40.

The starting material was prepared as follows:

A suspension of the (benzhydrylidene-amino)-phenol (10.47 g, 38.3 mmol),3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassium carbonate(5.82, 42.1 mmol) in 150 mL of acetone was heated at reflux overnight.The cooled reaction mixture was filtered and concentrated under reducedpressure. The residue was chromatographed on silica gel elutinghexanes/EtOAc (2:1). In this manner,3-[3-(benzhydrylidene-amino)phenoxy]-cyclohex-2-enone was obtained as ayellow solid, (8.82 g, 63%): ¹H NMR (CDCl₃) δ 7.78 (d, 2H, J=7.0 Hz),7.50 (d, 1H, J=7.1 Hz), 7.45 (d, 2H, J=7.7 Hz), 7.347.10 (m, 6H), 6.69(d, 1H, J=8.0 Hz), 6.61 (d, 1H, J=8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H),2.55 (t, 2H, J=6.2 Hz), 2.34 (t, 2H, J=6.2 Hz), 2.06 (m, 2H). Anal.Calc. for C₂₅H₂₁NO₂ 0.2H₂O: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12;H, 5.81; N, 3.72.

3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirredsolution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol(9.03 g, 82.8 mmol) in 25 mL toluene was heated at reflux with removalof H₂O with a Dean-Stark trap for 3.5 h. The crystals that formed fromthe cooled reaction mixture were collected by vacuum filtration, washedwith hexanes and air dried. In this manner,3-(benzhydrylidene-amino)phenol was obtained as a light yellow solid(17.3 g, 76%): ¹H NMR (CDCl₃) & 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H,J=7.1 Hz), 7.34-7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H, J=8.1Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz). Anal.Calc. for C₁₉H₁₅NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H,5.65; N, 5.03.

A solution of 3-[3-(benzhydrylidene-amino)phenoxy]-cyclohex-2-enone(4.37 g, 11.89 mmol) in 20 mL of THF was added slowly to a solution ofLiHMDS (25.0 mL of 1.0 M solution in THF) in 10 mL of THF at −78° C.Five minutes after the addition was complete trans-cinnamoyl chloride(1.98 g, 11.89 mmol) was added all at once, and stirring was continuedat −78° C. for 30 min. The reaction was quenched with saturated NH₄Clsolution. And extracted with EtOAc (2×). The combined organic layerswere washed with saturated NaCl solution, dried (MgSO₄) and concentratedunder reduced pressure. The residue was chromatographed on silica geleluting hexanes/EtOAc (5:1). In this manner,3-[3-(benzhydrylidene-amino)phenol]-6-(3-phenyl-acryloyl)cyclohex-2-enone was obtained as ayellow-orange solid (3.34 g, 56%): ¹H NMR(CDCl₃) o: 15.69 (s, 1H), 7.80(d, 2H, J=7.1 Hz), 7.63-7.01 (m, 15H), 6.93 (d, 1H, J=15.6 Hz), 6.75 (d,1H, J=7.6 Hz), 6.66 (d, 1H, J=8.0 Hz), 6.46 (s, 1H), 4.92 (s, 1H), 2.85(t, 2H. J=7.2 Hz), 2.62 (t, 2H, J=7.2 Hz). Anal. Calc. for C₃₄H₂₇NO₃: C,82.07; H, 5.47; N, 2.82. Found: C, 81.88; H, 5.53; N, 2.81.

To a stirred solution of3-[3(benzhydrylidene-amino)-phenol]-6-(3-phenyl-acryloyl)cyclohex-2-enone(1.81 g, 3.64 mmol) dissolved in 10 mL of HOAc/EtOH(1:1) was addedhydrazine hydrate (2.0 mL, 41.23 mmol). The solution was heated at 75°C. for 25 min. After cooling, the reaction mixture was cautiously pouredinto saturated sodium bicarbonate solution and extracted with EtOAc(2×). The combined organic layer was washed with saturated NaClsolution, dried (MgSO₄) and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting hexanes/EtOAc (1:1).3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was obtained asa yellow solid (539 mg, 45%). ¹H NMR (DMSO-d₆) δ 7.55 (d, 2H, J=7.2 Hz),7.38 (t, 2H, J=7.2 Hz), 7.27 (t, 1H, J=7.2 Hz), 7.05 (m, 3H), 6.38 (d,1H, J=8.0 Hz), 6.31 (s, 1H), 6.23 (d, 1H, J=7.9 Hz), 5.52 (s, 1H), 5.26(s, 2H), 2.92 (t, 2H, J=8.0 Hz), 2.58 (t, 2H, J=8.1 Hz). Anal. Calc. forC₂₁H₁₉N₃O.0.3H₂O: C, 75.33; H, 5.90; N, 1255. Found: C, 75.46; H, 5.96;N, 12.35.

To a stirred solution of 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)phenylamine (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (54 gi,0.31 mmol) in 5 mL of CH₂Cl₂, was added benzoyl chloride (36 W, 0.31mmol). After 15 mini, the reaction mixture was diluted with CH₂Cl₂ andwashed sequentially with 0.5N HCl, saturated sodium bicarbonate solutionand brine, dried (MgSO₄) and concentrated under reduced pressure. To astirred solution of the residue in 1,4-dioxane was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (35 mg, 0.15 mmol).After 1 h, the reaction mixture was concentrated under reduced pressureand the residue was chromatographed on silica gel eluting hexanes/EtOAc(2:1). In this manner,N-[3-(2-benzoyl-3-styrl-1H-indazol-6-yloxy)-phenyl]-benzamide wasprepared as a rust colored solid (90 mg, quantitative): ¹H NMR (CDCl₃) δ8.13 (s, 1H), 8.02 (d, 2H, J=7.0 Hz), 7.94 (d, 1H, J=8.7 Hz), 7.74 (d,2H, J=6.8 Hz), 7.57-7.19 (m, 17H), 6.84 (d, 1H, J=8.3 Hz).

Example 4(b) N-[3-(3-Styryl-1H-indazol-6-yloxy)-phenyl]-acetamide

Example 4(b) was prepared in a similar manner to that described forExample 4(a) above, except that acetic anhydride was used instead ofbenzoyl chloride in step (iv). ¹H NMR(DMSO-d₆) δ 13.08 (bs, 1H), 10.03(s, 1H), 8.22 (d, 1H, J=8.7 Hz), 7.72(d, 2H, J=7.3 Hz), 7.52 (s, 2H),7.447.27 (m, 6H), 7.01 (s, 1H), 6.96 (dd, 1H, J=8.7, 2.1 Hz), 6.78 (d,1H, J=6.9 Hz), 2.01 (s, 3H). Anal. Calc. for C₂₃H₁₉N₃O₂.0.25H₂O: C,73.88; H, 5.26; N. 11.24. Found: C, 74.20; H, 5.57; N, 10.82.

Example 5(a) 5-Methyl-thiazole-2-carboxylic acid{3-(3-styryl-1H-indazol-6-yloxy)-phenyl]-amide

A suspension of S-methyl-thiazole-2-carboxylic acid{3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-H-indazol-6-yloxyl-phenyl}amide(57 mg, 0.10 mmol) and potassium carbonate (50 mg, 0.36 mmol) in MeOHwas stirred at 23° C. for 20 nm. The solution was filtered, diluted withEtOAc and washed with brine (2×). The organic layer was dried (MgSO₄)and concentrated under reduced pressure. In this manner,5-methyl-thiazole-2-carboxylic acid{3-(3-styryl-1H-indazol-6-yloxy)-phenyl]-amide was prepared as a tansolid in 47% yield: ¹H NMR (DMSO-d₆) δ 13.00 (s, 1H), 10.80 (s, 1H),8.23 (d, 1H, J=8.8 Hz), 7.79 (s, 2H), 7.71 (t, 2H, J=8.6 Hz), 7.53 (s,2H), 7.41-7.27 (m. 5H), 7.04 (s. 1H), 7.00 (d, 1H, J=8.7 Hz), 6.89 (d,1H. J=8.5 Hz), 2.54 (s, 3H). Anal. Calc. for C₂₆H₂₀N₄O₂S 1.15H₂O: C,65.98; H. 4.75; N, 11.84; S. 6.78. Found: C, 65.99; H. 4.71; N, 11.58;S, 6.76.

The starting material was prepared as follows:

3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to5-methyl-thiazole-2-carboxylic acid(3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxy]-phenylamide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU(o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in DMF and analogous work-up, DDQ treatment andisolation to Example 4(a), step (iv) (50% yield): ¹H NMR(DMSO-d₆) δ10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H),7547.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).

Example 5(b)3-Methyl-N-[3-(3-styryl-1h-indazol-6-yloxy)-phenyl)-benzamide

Example 5(b) was prepared in a similar manner to that described forExample 5(a) above, except that m-tolylchloride was used in place of5-methyl-thiazole-2-carboxylic acid and HATU in step (i). ¹H NMR(DMSO-d₆) δ 13.04 (s, 1H), 10.28 (s, 1H), 8.23 (d, 1H, J=8.8 Hz),7.73-7.30 (m, 14H), 7.05 (s, 1H), 6.99 (d, 1H, J=8.5 Hz), 6.87 (d, 1H,J=7.7 Hz), 2.38 (s, 3H). Anal. Calc. for C₂₉H₂₃N₃O₂.0.2H₂O.0.2 hexanes:C, 77.78; H, 5.66; N, 9.01. Found: C, 77.80; H, 5.84; N, 8.93.

Example 6(a)N-(3-(3-[2-(4-Chloro-phenyl)-vinyl]-1H-indazol-6-yloxy)-phenyl)-benzamide

Starting fromN-(3-{1-benzoyl-3-[2-(4-chlorophenyl)-vinyl]-1H-indazol-6-yloxyl}-phenyl)-benzamide,the general procedure for example 5(a) was used to prepare the titlecompound as an off-white solid in 72% yield: ¹H NMR (DMSO-d₆) δ 3.07 (s,1H), 10.32 (s, 1H), 8.24 (d, 1H, J=8.8 Hz), 7.92 (d, 2H, J=7.1 Hz), 7.76(d, H, 1=8.5 Hz), 7.59-740 (m, 10H), 7.05 (s, 1H), 7.00 (d, 1H, J=8.7Hz), 6.87 (d, 1H, J=7.9 Hz). Anal. Calc. for C₂₈H₂₀ClN₃O₂.0.4H₂O.0.15hexanes; C, 71.41; H, 4.75; N, 8.65. Found: C, 71.62; H, 14.83; N, 8.45.

The starting material was prepared as follows:

Starting with 3-[3-(benzhydrylidene-amino)phenoxy]-cyclohex-2-enone and3-(4-chloro-phenyl)acryloyl chloride (prepared as described below), thegeneral procedure for Example 4(a), step (ii) was employed. The productwas used without purification in the hydrazine cyclization procedure,Example 4(a) step (iii), to give3-{3-[2-(4-chloro-phenyl)vinyl]4,5-dihydro-1H-indazol-6-yloxyl}-phenylamineas a yellow solid in 30% yield. ¹H NMR (DMSO-d₆) δ 12.45 (s, 1H), 7.58(d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 5.52 (s, 1H), 5.26 (s, 2H),2.92 (t, 2H, J=8.0 Hz), 2.58 (t, 2H, J=8.0 Hz). Anal. Calc. forC₂₁H₁₈ClN₃O. 0.75H₂O: C, 66.84; H, 5.21; N, 11.14. Found: C, 66.73; H,4.89; N, 11.01.

3-(4-chloro-phenyl)-acryloyl chloride was prepared as follows: To astirred suspension of 4-chloro-trans-cinnamic acid (251 g, 13.77 mmol)in benzene was added thionyl chloride (1.1 mL, 15.14 mmol) and acatalytic amount of DMAP. The reaction mixture was heated at reflux for1.5 h. The volatile materials were removed under reduced pressure. Thewhite residue was dissolved in Et₂O and concentrated again under reducedpressure, to give 3-(4-chloro-phenyl)-acryloyl chloride (2.78 g,quantitative) as a white solid: ¹H NMR (CDCl₃) δ 7.81 (d, 1H, 1=15.6Hz), 7.54 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6 Hz), 6.65 (d, 1H, J=15.6Hz).

3-{3-[2-(4-Chloro-phenyl)-vinyl]4,5-dihydro-1H-indazol-6-yloxyl}-phenylaminewas converted intoN-(3-{1-benzoyl-3-[2-(4-chloro-phenyl)-vinyl]-1H-indazol-6-yloxyl}-phenyl)-benzamideby the procedure described in Example 4(a), step (iv) (85% yield). ¹HNMR (DMSO-d₆) δ 10.37 (s, 1H), 8.43 (d, 1H, J=8.8 Hz), 8.00-7.39 (m,21H), 7.34 (d. 1H, J=8.8 Hz), 6.93 (d, 1H, J=8.8 Hz).

Example 6(b)N-[3-[3-(2-Indolyl)-1H-indazol-6-yloxy]-phenyl)-3-methyl-benzamide

Example 6(b) was prepared in a similar manner to that described forExample 6(a) above, except that 1-SEM-indazole-2-carboxylic acid wasused in step (i) in place of 4-chlor-trans-cinnamic acid. ¹H NM(DMSO-d₆) δ 13.19 (s, 1H), 11.59 (s, 1H), 10.29 (s, 1H), 8.23 (d, 1H,J=8.7 Hz), 7.73-7.38 (m. 9H), 7.12 (s, 1H), 7.03 (d, 2H, J=7.3 Hz), 6.88(d, 1H, J=7.8 Hz), 2.38 (s, 1H). HRMS [m+H]/z Calc'd: 459:1821, found459.1836.

Example 7 3-(Styryl-1H-indazol-6-yloxy)-phenylamine

A suspension of 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine(75 mg, 0.23 mmol) and 90 mg of 5% palladium on carbon (Pd/C) was heatedat 155° C. After 4 h, more 5% Pd/C (39 mg) was added. After 22 h, more5% Pd/C (30 mg) was added. The reaction mixture was filtered while hotafter 26 h. The catalyst was washed and the filtrate concentrated underreduced pressure. The residue was chromatographed on silica elutinghexanes/EtOAc (1:1). The appropriate fractions were concentrated andtriturated with CH₂Cl₂/hexanes to give the title compound as anoff-white solid (20 mg, 27%): ¹H NMR (DMSO-d₆) δ 8.16 (d, 1H, J=85 Hz),7.71 (d, 2H, J=6.7 Hz), 7.50 (s, 2H), 7.40 (t, 2H, J=7.0 Hz), 7.30 (d,H, J=6.5 Hz), 7.060.92 (m, 3H), 6.35 (d, 1H, J=8.3 Hz), 6.23 (s, 2H),5.26 (s, 2H). Anal. Calc. for C₂₁H₁₇N₃O.0.15CH₂Cl₂: C, 74.69; H, 5.13;N, 12.36. Found: C, 74.64; H, 5.23; N, 12.25.

Example 8(a) 3-(E-styryl)-6-phenoxy-1H-indazole

A suspension of 3-(E-styryl)-6-phenoxy-4,5-dihydro-1H-indazole (200 mg.0.64 mmol) and 5% Pd/C (200 mg) in 10 mL of tetralin was heated at 155°C. for 18 h. The catalyst was removed by filtering the hot solution andwashed with THF, EtOAc and MeOH. The filtrate was concentrated underreduced pressure and the residue was chromatographed on silica geleluting hexanes/EtOAc (2:1) to provide 3-(E-styryl)& phenoxy-1H-indazoleas an off-white solid (110 mg, 55%). ¹H NMR (DMSO-d₆) δ 6.96 (s, 2H),7.10 (d, 2H, J=7.7 Hz), 7.20 (t, 1H, J=7.1 Hz), 7.30 (t, 1H, J=7.1 Hz),7.44 (m, 6H), 7.71 (d, 2H, J=7.5 Hz), 8.20 (d, 1H, J=9.2 Hz), 12.90 (s,1H). Anal. Calc. for C₂₁H₁₆N₂O 0.1H₂O: C, 80.28; H, 5.20; N, 8.92.Found: C, 80.20; H, 5.21; N, 8.93.

The starting material was prepared as follows:

-   -   (i) To a stirred solution of 3-chloro-cyclohex-2-enone (3.00 g,        23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone        was added powdered, anhydrous K₂CO₃ (3.81 g, 27.6 mmol). After        refluxing for 18 h, the mixture was cooled and filtered. The        filtrate was concentrated under reduced pressure and        chromatographed on silica gel eluting with hexanes/EtOAc (4:1)        to give 3-phenoxy-cyclohex-2-enone as a white solid: ¹H NMR        (CDCl₃) δ 2.10 (quint, 2H, J=6.3 Hz), 2.40 (t, 2H, 1=6.2 Hz),        2.68 (t, 2H, J=6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H, J=7.5 Hz),        7.26 (t, 1H, J=7.3 Hz), 7.41 (t, 2H, J=7.6 Hz).    -   (ii) A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol)        in 1 mL of THF was added to a stirred solution of 1.0 M solution        of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C.        After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added        all at once. After 15 min, the reaction mixture was poured into        0.5 N HCl and extracted with EtOAc (2×). The combined organic        layers were washed with saturated NaCl solution, dried (MgSO₄),        filtered, and concentrated under reduced pressure.        Chromatography of the residue with 4:1 hexanes/ethyl acetate as        eluant provided 220 mg (43%) of        3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-none as a yellow        solid (220 mg, 43%): ¹H NMR (CDCl₃) (enol form) δ 2.66 (t, 2H,        J=7.2 Hz), 2.84 (t, 2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H,        J=15.6 Hz), 7.02 (d, 2H, J=8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m,        3H). HRMS M+H⁺ calc: 319.1334, found 319.1340.    -   (iii) To a stirred solution of        3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55        mmol) in 20 mL of HOAc/EtOH(1:1) was added hydrazine monohydrate        (0.21 mL, 4.3 mmol). The reaction was heated at 70° C. for 3 h,        cooled and poured cautiously into saturated Na HCO₃ solution and        extracted with EtOAc (2×). The combined organic layers were        washed with saturated NaCl solution, dried (MgSO₄) and        concentrated under reduced pressure. The residue was        chromatographed on silica gel eluting hexanes/EtOAc (2:1) to        give 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an        off-white solid (406 mg, 36%): ¹H NMR (DMSO d₆) δ 2.64 (t, 2H        J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 5.46 (s, 1H), 7.04 (AB, 2H,        J=16.8 Hz), 7.15 (d, 2H, J=8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H),        7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H). Anal. Calc. for C₂H₁₈N₂O        0.2H₂O: C, 79.32; H, 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N,        8.84.

Example 8(b) 3-(E-styryl)-6-[4-(methoxymethoxy)phenoxy]-1H-indazole

Example 8(b) was prepared in a similar manner to that described forExample 8(a) above, except that 4(methoxymethoxy)phenol was used inplace of phenol in step (i). ¹H NMR (DMSO-d₆) δ 12.90 (s, 1H), 8.17 (d,1H, J=8.8 Hz), 7.71 (d, 2H, J=7.6 Hz), 7.50 (s, 3H), 7.41 (t, 2H, J=7.6Hz), 7.31 (d, 1H, J=7.4 Hz), 7.10 (s, 3H), 6.95 (dd, 1H, J=8.8, 1.9 Hz),6.84 (s, 1H), 5.20 (s, 2H), 3.42 (s, 3H). Anal. Calc. for C₂₃H₂₀N₂O₃: C,74.17; H, 5.41, N. 7.52. Found: C, 74.21; H, 5.59; N, 7.46.

Example 8(c) 3-(E-styryl)-6-phenylsulfanyl-1H-indazole

Example 8(c) was prepared in a similar manner to that described forExample 8(a) above, except that thiophenol was used in step (i) in placeof phenol. ¹H NMR (DMSO-d₆) δ 7.29 (d, 1H, J=8.5 Hz), 7.45-7.59 (m, 9H),7.67 (s, 2H), 7.86 (d, 2H, J=7.2 Hz), 8.35 (d, 1H, J=8.5 Hz), 13.30 (s,1H). Anal. Calc. For C₂₁H₁₆N₂S, 0.25H₂O: C, 75.76; H. 5.00; N, 8.41; S,9.63. Found: C, 75.79; H. 4.99; N, 8.16; S, 9.63.

Example 8(d) 6-(3-Bromo-phenoxy)-3-styryl-1H-indazole

Example 8(d) was prepared in an analogous manner to that described forExample 8(a) above, except that 3-bromophenol was used in step (i) inplace of phenol. ¹H NMR (DMSO d) δ 13.08 (s, 1H), 8.23 (d, 1H, J=8.8Hz), 7.72 (d, 2H, J=7.3 Hz), 7.53 (s, 2H), 7.43-7.35 (m, 4H), 7.30 (t,2H, J=7.2 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.09 (s, 1H), 6.98 (d, 1H, J=8.8Hz). Anal. Calc. for C₂₁H₁₅BrN₂O: C, 64.46; H, 3.86; Br, 20.42; N, 7.16.Found: C, 64.31; H, 3.99; Br, 20.52; N, 7.11.

Example 9(a) 3-(E-styryl)-6-[3-hydroxyphenoxy]-1H-indazole

To a stirred solution of3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole (50 mg, 0.13mmol) in 5 mL CH₂Cl₂ at −25° C. was added trimethylsilylbromide (75 μl,0.57 mmol). After 1.5 h, saturated NaHCO₃ solution was added and theproduct was extract with EtOAc (2×). The combined organic layers werewashed with saturated NaCl solution, dried (MgSO₄) and concentratedunder reduced pressure. The residue was chromatographed on silica geleluting hexanes/EtOAc (1:1) to give, after trituration withCH₂Cl₂/hexanes, 3-(E-styryl)-6-(3-hydroxyphenoxy]-1H-as an off-whitesolid (22 mg, 50%): ¹H NMR (DMSO-d₆) δ 6.37 (s, 1H), 6.43 (d, 1H, J=8.1Hz), 6.50 (d, 1H, J=8.1 Hz), 6.88 (d, 1H, J=8.8 Hz), 6.92 (s, 1H), 7.12(t, 1H, J=8.1 Hz), 7.24 (t, 1H, J=7.3 Hz), 7.31 (t, 2H, J=7.6 Hz), 7.44(s, 2H), 7.64 (d, 2H, J=7.5 Hz), 8.12 (d, 1H. J=8.7 Hz), 9.54 (s, 1H),12.92 (s, 1H). Anal. Calc. For C₂₁H16N₂O₂.0.3H₂O: C, 75.57; H. 5.01; N.8.39. Found: C, 75.74; H, 5.11; N. 8.25.

The starting material,3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole, was prepared asdescribed in Example 8(b).

¹H NMR (CDCl₃) δ 3.42 (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H, J=8.2 Hz),6.72 (s, 1H), 6.80 (d, 1H, J=8.3 Hz), 6.98 (s, 1H), 7.00 (d, 1H. J=8.8Hz), 7.19-7.38 (m, 5H), 7.53 (m, 3H), 7.92 (d, 1H, J=8.9 Hz). Anal.Calc. For C₂₃H₂₀N₂O₃: M+H⁺: 373.1552, found 73.1546

Example 9(b) 3-(E-styryl)-6-[4-hydroxyphenoxy]-1H-indazole

Example 9(b) was prepared like Example 9(a) above, except that3-(E-styryl) 6[4(methoxymethoxy)phenoxy]-1H-indazole was used in placeof 3(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-1H-indazole. ¹H NMR(DMSO-d₆) δ 12.95 (s, 1H), 9.58 (s, 1H), 8.33 (d, 1H, J=9.0 Hz), 7.89(d, 2H, J=7.1 Hz), 7.68 (s, 1H), 758 (t, 1H, J=7.3 Hz), 7.48 (d, 1H,J=7.3 Hz), 7.24 (s, 1H), 7.13 (m, 3H), 6.99 (d, 2H, J=8.8 Hz). HRMS[m+H]/z Calc'd: 329.1290. Found: 329.1293. Anal. Calc. forC₂₁H₁₆N₂O₂.0.35H₂O: C, 75.36; H, 5.03; N, 8.37. Found: C, 75.35; H,5.22; N, 8.24.

Example 10 6-(1-Phenyl-vinyl)-3-styryl-1H-indazole

6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(16.2 mg, 0.0358 mmol) was dissolved in THF (0.6 mL) and was treatedwith tetrabutylammonium fluoride (TBAF, 1M in THF, 0.6 mL). The mixturewas heated to 60° C. under argon for 4 h. The mix was cooled,neutralized with excess saturated sodium bicarbonate and the organicmaterial was extracted into ethyl acetate and concentrated. This mix of3 compounds (by TLC visualization) was treated with THF-water-TFA(1:1:2, 4 mL) for 30 min. The mix was diluted with toluene (20 mL),concentrated, neutralized with excess saturated sodium bicarbonate, andthe organic material was extracted into ethyl acetate. The organicmaterial was dried over sodium sulfate, decanted and concentrated.Purification by silica gel chromatography (2:8 ethyl acetate-hexane)gave 6-(1-Phenyl-vinyl)-3-styryl-1H-indazole (4.6 mg, 40%): R_(f) sm0.62, p 0.24 (ethyl acetate-hexane 3:7); ¹H NMR (300 MHz, CDCl₃) δ 7.99(d, 1H, J=8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, 1H, J=1.1 Hz), 5.56 (d,1H, J=1.1 Hz); HRMS (FAB) [m+H]/z Calc'd 323.1548, Found 323.1545.

The starting material was prepared as follows:

6-Iodoindazole was converted to 3,6-diiodoindazole (82%) as described inExample 1(a), step (v): ¹H NMR (300 MHz, CDCl₃) δ 10.3 (bs, 1H), 7.90(s, 1H), 7.52 (dd, 1H, J 1.2, 8.5 Hz), 7.24 (d, 1H, J=8.5 Hz).

3,6-Diiodoindazole (755 mg, 2.04 mmol) was added to 50% KOH (2.5 g in2.5 mL water) at 0° C. and dichloromethane (4 mL) was added. To thismixture was added tetrabutylammonium bromide (TBABr, 6.6 mg, 0.02 mmol,0.01 equiv) and 2-(trimethyl-silanyl)ethoxymethyl chloride (SEM-Cl, 397μL, 2.24 mmol, 1.10 equiv) was added dropwise over a 3 min period. Themixture was stiffed rapidly at 0° C. for 1.5 h. Water (20 mL) anddichloromethane (20 mL) were added and the organic material wasseparated, dried over sodium sulfate and concentrated. Silica gelchromatography (5% ethyl acetate in hexane; 150 mL silica) gave 2isomeric compounds (1-SEM, 763 mg, 75%; and 2-SEM, 105 mg, 10%): R_(f)sm 0.08, p 0.34 and 0.27 (ethyl acetate-hexane 1:9); ¹H NMR (300 MHz,CDCl₃) δ 8.0 (s, 1H), 755 (d, 1H, J=8.5 Hz), 7.24 (d, 1H, J=8.5 Hz),5.69 (s, 2H), 3.58 (t, 2H J=8.2 Hz), 0.90 (t, 2H, =8.2 Hz), 0.1 (s, 9H).

1-Bromostyrene (26 μL, 0.20 mmol, 2.0 equiv) was dissolved in THF (0.75mL), cooled to −78° C. and was treated with t-BuLi (235 μL, 0.40 mmol,1.70 M, 4.0 equiv). The mixture was allowed to warm to −42° C. for 10min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol, 2.5equiv). The resulting solution was allowed to warm to 23° C. withstirring for 25 min. This mix was added to a mixture of neat3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (50 mg,0.10 mmol, 1 equiv) and Pd(PPh₃)₄ (5 mg, 0.004 mmol, 0.04 equiv). After10 min the reaction was determined to be complete by TLC monitoring andwas quenched with saturated sodium bicarbonate. Organic material wasextracted into ethyl acetate, dried over sodium sulfate and concentratedunder reduced pressure. Silica gel chromatography (5:95 ethylacetate-hexane) provided3-Iodo-&6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(33.1 mg, 70%): R_(f) sm 0.39, p 0.36 (ethyl acetate-hexane 1:9); ¹H NMR(300 MHz, CDCl₃) δ 7.50 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.33 (m, 5H),7.22 (dd, 1H, J=1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J=1.0 Hz), 5.57(d, 1H, J=1.0 Hz), 3.58 (t, 2H, J=8.2 Hz), 0.88 (t, 2H, J=8.2 Hz), −0.09(s, 9H); HRMS (FAB) [m+H]/z Calc'd 477.0859, found 477.0866.

Preparation of 6-(1-Phenyl-vinyl)-3-styryl1-[2-(triethyl-silanyl)-ethoxymethyl]-1H-indazole: E-2-Bromostyrene (23μL, 0.174 mmol, 2.5 equiv) was dissolved in THF (1.0 mL) and was cooledto −78° C. t-BuLi (205 μL, 0.348 mmol, 5.00 equiv) was added and themixture was warmed to 42° C. for 7 min to give a deep red mixture. Thesolution was added to freshly dried zinc chloride (29 mg, 0.209 mmol,3.00 equiv) via cannula and the mix was allowed to warm to 23° C. withstirring for 20 min. This solution was added to a neat mixture of3-Iodo-61-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(33.1 mg, 0.0696 mmol, 1.0 equiv) and Pd(PPh₃)₄ (4 mg, 0.0035 mmol, 0.05equiv) at 23° C. via cannula. This solution was allowed to stir for 15min and was treated with saturated sodium bicarbonate and extracted withethyl acetate. The organic material was dried over sodium sulfate,decanted and concentrated. Purification by silica gel chromatographyusing two columns (5:95 ethyl acetate-hexane; 12 ml silica: and 1:99ethyl acetate-benzene; 12 mL silica) gave6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(16.2 mg, 51%): R_(f) sm 0.38, p 0.29 (ethyl acetate-hexane 1:9); ¹H NMR(300 MHz, CDCl₃) δ 7.98 (d, 1H, J=8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s,2H), 5.57 (s, 2H), 3.60 (t, 2H, J=8.2 Hz), 0.90 (t, 2H, J=8.2 Hz), −0.08(s, 9H); HRMS (FAB) [m+H]/z Calc'd 453.2362, Found 453.2354.

Example 11 N-Methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine

ToN-methyl-N-(3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl)-benzene-1,3-diamine(237 mg, 0.5 mmol) was added 1M TBAF in THF (10.1 mL, 10.1 mmol),followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). Theresulting mixture was heated to 70° C. for 5 h. The reaction was thenquenched with saturated NaHCO₃ (10 mL) and extracted 3×35 mL EtOAc. Thepooled EtOAc phase was washed 5×20 mL H₂O, then brine (20 mL), driedwith Na₂SO₄, decanted and concentrated under reduced pressure to a foam.The crude material was purified by silica gel chromatography (9; 1dichloromethane/ethyl acetate) to giveN-methyl-N-3-styryl-1H-indazolyl)-benzene-1,3-diamine as a foam (120 mg,70% yield). Rf sm 0.73, Rf p 0.27 (dichloromethane:ethylacetate 7:3);¹³C NMR (75 MHz, CDCl₃) δ 150.3, 148.8, 147.5, 147.5, 143.9, 143.4,137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0, 120.5,117.0, 116.0, 112.6, 109.8, 109.0, 98.3, 40.7; LCMS (ESI) [M+H]/z Calc'd341, Found 341. Anal. Calc'd: C, 77.62; H, 5.92; N, 16.46. Found: C,76.16; FL 5.88; N, 15.95.

Starting material prepared as follows:

6-nitro-1H-indazole was converted to 3-Iodo-6-nitro-1H-indazole asdescribed in Example 1(a), step (v) (50.6 g, 87%): FTIR (KBr) 3376,3076, 2964, 2120, 1739, 1626, 1526, 1439, 1294, 1128, 954 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 8.28 (s, 1H), 8.05 (s, 1H), 7.66 (d, 1H, J=8.13 Hz),7.45 (dd, 1H, J=8.33, 1.38 Hz), 7.17 (d, 1H, J=1.01 Hz), 7.14 (s, 1H),7.03 (d, 1H, J=8.04 Hz), 6.89 (s, 2H), 3.82 (s, 3H), 2.55 (s, 6H), 2.21(s, 3H) 1.32 (s, 9H). MS (FAB) [M+H]/z Calc'd 311, Found 311. Anal.Calc'd: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.41; H, 5.98; N, 8.79.

3-Iodo-6-nitro-1H-indazole was converted to6-Nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole asdescribed in Example 10, step (ii) (10.2 g, 81% yield): mp 58° C. Anal.Calc'd: C, 37.24; H, 4.33; N, 10.02. Found: C, 37.21; H, 4.38; N, 10.00.

To 6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (11.0g, 26.1 mmol), styryl boronic acid (4.64, 31.4 mmol), and Pd(PPh₃)₄(1.25 g, 1.08 mmol) under an atmosphere of argon was added toluene (192mL), MeOH (4 mL) and 2N NaOH (aq) (32.6 mL, 65.3 mmol). The resultingheterogeneous mixture was heated to 90° C. After 8 h the reaction wasdiluted with EtOAc (150 mL) and water (50 mL), the phases were separatedand the organic was extracted 2×50 mL EtOAc. The pooled organic phasewas washed with brine (50 mL), then dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The crude reaction was purified bysilica gel chromatography (1:9 EtOAc:hexane) to give6-nitro-3-styryl-1-[2-(trimethyl-silanyl) ethoxymethyl]-1H-indazole as ayellow solid (7.65 g, 74%): ¹³C NMR (75 MHz, CDCl₃) δ 148.3, 145.0,141.3, 138.1, 134.2, 130.5, 129.9, 129.8, 129.5, 128.1, 127.4, 123.2,119.8, 117.8, 108.2, 79.7, 68.5, 19.2, 0.0; MS (FAB) [M+Na]/z Calc'd418, found 418. Anal. Calc'd: C, 63.77; H. 6.37; N. 10.62. Found: C,64.04; H, 6.29; N, 10.56.

6-Nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (8.1g, 205 mmol) was dissolved in DMF (75 mL) at 23° C. under an atmosphereof argon. SnCl₂ (12.9 g, 67.7 mmol) was added followed by water (1.7 mL,92.2 mmol) and the resulting mixture was heated to 50° C. After 4 h, 3NNaOH (45 mL, 135 mmol) was added followed by EtOAc (100 m]L). Theresulting emulsion was filtered hot through Celite and the bed of Celitewas washed with hot EtOAc (3×100 mL). The filtrate was concentratedunder reduced pressure, the residue was dissolved in EtOAc, washed withbrine, dried with Na₂SO₄, filtered and concentrated under reducedpressure to give a solid. The crude material was purified by silica gelchromatography (2:8→7:3 ethyl acetate:hexane), to give3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine asa yellow solid (5.1 g, 68% yield). MS (FAB) [M+H]/z Calc'd 366, found366.

To 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine(1.1 g, 3 mmol, m-nitro-iodobenzene (0.9 g, 3.6 mmol), BINAP (0.07 g,0.133 mmol), Pd₂(dba)₃ (34 mg, 0.0375 mmol) and Cs₂CO₃ (1.37 g, 4.2mmol) under an atmosphere of argon was added toluene (6 mL). Theresulting heterogeneous mixture was heated to 80° C. After 46 h thereaction was cooled to 23° C. diluted with ethyl acetate (EtOAc) (20 mL)and filtered. Water (5 mL) was added, the phases were separated, and theorganic was extracted 2×50 mL EtOAc. The pooled organic material waswashed with brine, then dried with Na₂SO₄, filtered and concentratedunder reduced pressure. The crude reaction was purified by silica gelchromatography (eluting with 9:1 hexane:EtOAc) to give(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amineas a yellow solid (7.65 g, 74%): TLC (Hexane:EtOAc 7:3) Rf sm 0.16, Rf p0.30 (ethyl acetate:hexane 3:7); FTIR (KBr) 3391, 3059, 2952, 2894,1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 7.86 (s, 1H), 7.83 (s. 1H), 7.65 (dt, 1H, J=2.21, 5.13 Hz),7.15-7.41 (m, 5H), 6.93 (dd, 1H, J=1.87, 8.67 Hz), 5.56 (s, 2H), 3.51(t, 2H, J=8.17 Hz), 0.81 (t, 2H, J=7.96 Hz), −0.15 (s, 9H); ¹³C NMR (75MHz, CDCl₃) δ 149.6, 144.8, 143.5, 142.4, 140.9, 137.3, 131.8, 130.3,129.0, 128.2, 126.7, 122.8, 122.6, 120.1, 119.3, 116.1, 115.6, 111.4,98.5, 77.9, 66.7, 18.0, −1.2; MS (ESI) [M+H]/z Calc'd 487, found 487.Anal. Calc'd: C, 66.64; H, 6.21; N, 11.51. Found: C, 66.91; H, 6.21; N,11.44.

To(3-nitro-phenyl)-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolyl)-amine(434 mg, 0.89 mmol) in THF (5 mL) cooled to −5° C. under an atmosphereof argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed byLiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction wasquenched with saturated NH₄Cl(aq) (2 mL), then extracted 3×20 mL EtOAc.The pooled organic material was washed with brine (10 mL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. Purificationby silica gel chromatography (eluting with hexane:EtOAc 9:1) gavemethyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl}-amine,as an oil (367 mg, 82%): TLC (Hexane:EtOAc 7:3) Rf sm 0.29, Rf p 0.39(ethyl acetate:hexane 3:7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485,1348, 1248, 1077 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, 1H, J=8.67 Hz)7.77 (t, 1H, J=2.25 Hz), 7.72 (dd, 1H, J=0.79, 2.09 Hz), 7.60, (d, 2H,J=7.22 Hz), 7.26-7.54 (m, 7H), 7.19 (dd, 1H, J=0.78, 2.41 Hz) 7.07 (dd,1H, J=1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J=8.10 Hz), 3.48 (s,3H), 0.92 (t, 2H, J=8.10 Hz), −0.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2,126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0,66.8, 41.1, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 501, Found 510.

Methyl-(3-nitro-phenyl}{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-aminewas converted to N-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl)-benzene-1,3-diamine as described inExample 11, step (iv). Rf sm 0.55, Rf p 0.31 (ethyl acetate:hexane 3:7);FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249,1074 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, 1H, J=8.8 Hz) 7.58 (d, 2H,J=7.21 Hz), 7.26-7.50 (m 5H), 7.12 (t, 1H, J=7.93 Hz), 7.01 (d, 1H,J=1.73 Hz), 6.95 (dd, 1H, J=1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H,J=8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, J=8.13 Hz), −0.04 (s, 9H); ¹³CNMR (75 MHz, CDCl₃) δ 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3,130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1,109.3, 97.5, 77.8, 66.6, 41.0, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd471, Found 471.

Example 12(a)N-(3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl)-acetamide

N-Methyl-N-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl-benzene-1,3-diamine,prepared in Example 11 (34 mg, 0.041 mmol) was suspended in CH₂Cl₂ (0.5mL) at 23° C. under an atmosphere of argon. Pyridine (81 μl, 1.0 mmol),Ac₂O (94 μl, 1.0 mmol) and DMAP (cat.) were added. The reaction becamehomogeneous immediately. After 1 h, TLC analysis (CH₂Cl₂:EtOAc 4:1)indicated no starting material. The reaction was quenched with saturatedNaHCO₃(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phasewas washed with brine (3 mL), decanted and concentrated under reducedpressure to an oil. The oil was suspended in MeOH (2 mL) and K₂CO₃ (83mg, 0.6 mmol) was added. The resulting mixture was stirred at 23° C.under an atmosphere of argon. After 1 h, the reaction was diluted withEtOAc (15 mL) and the organic phase was washed with brine (3 mL),decanted and concentrated under reduced pressure. The crude material waspurified by semi-prep HPLC to giveN-{3-[methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-acetamide (8.4mg, 22%). ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H, J=8.68 Hz), 7.58 (d,1H, J=7.17 Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, J=8.29 Hz), 6.98 (m,1H), 6.95 (d, 1H, J=1.92 Hz), 6.8 (dd, 1H, J=1.16, 8.05 Hz), 3.37 (s,3H), 2.14 (s, 3H). LCMS (ESI) [M+H]/z Calc'd 383, Found 383. Anal.Calc'd: C, 75.37; H, 5.80; N. 14.65. Found: C, 73.53; H, 6.01; N, 13.73.

Example 12(b)N-(3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl)-benzamide

Example 12(b) was prepared in a similar manner to that described forExample 1012(a) above, except that benzoyl chloride was used instead ofacetic anhydride. LCMS (ESI) [M+H]/z Calc'd 475, found 475. Anal. Calc'dC (78.36), H (5.44), N (12.60). Found: C (76.57), H (5.0), N (12.12).

Example 12(c){3-[Methyl-(3-styryl-1H-indazol-6-yl)-amino)-phenyl}-carbamic acidbenzyl ester

Example 12(c) was prepared in a similar manner to that described forExample 12(a) above, except that carbobenzyloxy chloride was usedinstead of acetic anhydride. Rf sm 0.30, Rf p 0.57 (CH₂Cl₂:EtOAc 8:2);LCMS (ESI+) [M+H]/z Calc'd 475 Found 475; Anal. Calc'd C (75.93), H(5.52), N (11.81) Found, C (75.60), H (5.96), N (10.75).

Example 12(d) 5-Methyl-thiazole-2-carboxylic acid(3-[methyl-(3-styryl-1H-indazolyl)-6-yl)-amino]-phenyl}-amide

To a solution ofN-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine, prepared inExample 11, (26 mg, 0.075 mmol) and 5-methyl-thiazole-2-carboxylic acid(64 mg, 0.45 mmol) in DMF (0.375 mL) at 23° C. under an atmosphere ofargon was added HATU (171 mg, 0.45 mmol). After 1 h, TLC analysis(CH₂Cl₂:EtOAc 8:2) indicated no starting material. The reaction wasquenched with saturated NaHCO₃(aq) (2 mL) then diluted with EtOAc (15mL) and the organic phase was washed with brine (3 mL), decanted andconcentrated under reduced pressure. The oil was suspended in MeOH (2mL) and K₂CO₃ (62 mg, 0.45 mmol) was added. The resulting mixture wasstirred at 23° C. under an atmosphere of argon. After 1 h TLC analysis(CH₂Cl₂:EtOAc 8:2) indicated no starting material. The reaction wasdiluted with EtOAc (15 mL) and the organic phase was washed with brine(3 mL), decanted and concentrated under reduced pressure to a solid. Thecrude material was purified by silica gel chromatography (eluting withCH₂Cl₂:EtOAc 85:15) to give the title compound after purification bysemi-prep. HPLC (9.9 mg, 28%). Rf sm 0.25, Rf p 0.39 (hexane:EtOAc 8:2);LCMS (ESI+) [M+H]/z Calc'd 466, found 466. Anal. Calc'd C (69.65). H(4.98), N (15.04) S (6.89). Found: C (69.24), H (5.35), N (13.97) S(5.95).

Example 13 N-[3-(3-Styryl-1H-indazol-ylamino)-phenyl]-benzamide

N-(3-(3-Styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-amino]-phenyl)benzamidewas converted to N-[3-(3-styryl-H-indazol-6-ylamino)-phenyl]-benzamideas described in Example 11. LCMS (ESI) [M+H]/z Calc'd 431, found 431.Anal. Calc'd: C, 78.12; H, 5.15; N, 13.01. Found: C, 77.06; H, 6.91; N,9.88.

The starting material was prepared as follows:

(3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine,prepared in Example 11, step (vi), was converted toN-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamineas described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc'd 457,found 457.

To a solution ofN-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine(91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH₂Cl₂ (0.5 mL)cooled to −5° C. under an atmosphere of argon was added benzoyl chloride(0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched withsaturated NaHCO₃(aq) then extracted 2×5 mL CH₂Cl₂. The pooled organicmaterial was washed with brine (5 mL), dried with Na₂SO₄, decanted andconcentrated under reduced pressure to give an oil. The crude materialwas purified by silica gel chromatography (eluting with hexane:EtOAc3:2) to giveN-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl)-1H-indazol-6-ylamino}-phenyl)-benzamide(108 mg, 96% yield). Rf sm 0.35, Rf p 0.44 (ethyl acetate:hexane 1:1);FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303,1248, 1074 cm−1; LCMS (ESI) [M+H]/z Calc'd 561, Found 561. Anal. Calc'd:C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.

Example 14 Methyl-phenyl-(3-styryl-1H-indazol-6-yl)-amine

Methyl-phenyl-(3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazolyl)-amine was converted tomethyl-phenyl-(3-styryl-1H-indazol-6-yl)-amine as described in Example11. MS (ESI) [M+H]/z Calc'd 326, found 326.

The starting material was made as follows:

To a solution of3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine(1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl(1.67 mL) cooled to 2° C. was added a solution of NaNO₂ (304 mg, 4.4mmol) in water (05 mL) over 5 min. The resulting dark red solution wasstirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and12 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keepthe internal temperature below 5° C. After 2 h at 2° C. the reaction wasallowed to stir at 23° C. for 17 h. The reaction was quenched with 3 NNaOH (aq), diluted with EtOAc (50 mL) and H₂O (15 mL), the phases wereseparated and the aqueous was extracted 2×15 mL EtOAc. The pooledorganic phase was washed 3×20 mL 5% NaHSO₃, brine (15 mL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. The crudereaction was purified by silica gel chromatography (eluting with 1:1hexane:EtOAc) to give6-iodo-3-styryl-t-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as awhite solid (1.3 g, 68% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.03 (s, 1H),7.79 (d, 1H, J=9.0 Hz), 7.30-7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H,J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); ¹³C NMR (75 MHz, CDCl₃) δ143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4,119.6, 119.5, 92.9, 78.1, 66.9, 18.0, −1.2. Anal. Calc'd: C, 52.94; H,5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.

6-Iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole wasconverted tomethyl-phenyl-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl)-amineas described in Example 11, step (v). Rf sm 0.35 Rf p 0.13 (EtOAc:hexane1:9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248,1212, 1076, 835, 694 cm⁻¹; MS (ESI) [M+H]/z Calc'd 456, Found 456.

Example 15N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-Indazol-6-yl]-N-methyl-benzene-1,3-diamine

[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-yl]-methyl-(3-nitro-phenyl)amine was converted toN-[3-(2-benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamineas described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc'd 385,found 385. Anal. Calc'd: C, 71.86; H, 5.24; N, 14.57. Found: C, 70.99;H, 5.60; N, 13.80.

The starting material was prepared as follows:

To a mixture of6-nitro-3-iodo-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole (4.2 g,10 mmol), boronic acid (3.46 g, 15 mmol), and Pd(PPh₃)₄ (0.58 g, 0.5mmol) at 23° C. under an atmosphere of argon was added 1,4-dioxane (38mL) and 2N NaOH (aq) (12.5 mL, 25 mmol). The resulting mixture washeated to 90° C. After 2 h the reaction was diluted with EtOAc (100 mL)and water (70 mL), the phases were separated and the organic wasextracted 2×100 mL EtOAc. The pooled organic phase was washed with brine(20 mL) then dried with Na₂SO₄, filtered and concentrated under reducedpressure. The crude mixture was purified by silica gel chromatography(eluting with 9:1 hexane:EtOAc) to give3-(2-benzo[1,3]dioxol-5-yl-vinyl)-6-nitro-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazoleas a yellow solid (4.15 g, 94% yield). FTIR (thin film) 2950, 2898,1523, 1501, 1483, 1446, 1344, 1249, 1080, 1043, 927 cm¹; ¹H NMR (300MHz, CDCl₃) δ 8.56 (dd, 1H, J=0.68, 1.75 Hz), 8.14 (d, 1H, J=1.78 Hz),8.13 (d, 1H, J=0.67 Hz), 7.50 (d, 1H, 16.53 Hz), 7.25 (d, 1H, 16.52 Hz),7.18 (d, 1H, J=1.67 Hz), 7.07 (dd, 1H, J=1.65, 8.13 Hz), 6.88 (d, 1H,J=8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, J=7.33 Hz), 0.97 (t,2H, J=7.24 Hz), 0.0 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 148.5, 148.2,147.0, 143.9, 140.1, 132.7, 131.3, 126.1, 122.3, 121.9, 116.7, 116.5,108.7, 106.9, 105.7, 1015, 78.4, 67.2, 17.9, −1.3; LCMS (ESI) [M+H]/zCalc'd 531, found 531.

3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-ylamineas described in Example 11, step (iv). ¹H NMR (300 MHz, CDCl₃) δ 7.73(d, 1H, J=8.56 Hz), 7.52 (d, 1H, J=16.57 Hz), 7.18 (d, 1H, J=16.56 Hz),7.10 (d, 1H, J=1.49 Hz), 6.98 (dd, 1H, J=1.52, 8.06 Hz), 6.80 (d, 1H,J=8.01 Hz), 6.68 (d, 1H, J=1.44 Hz), 6.63 (dd, 1H, J=1.86, 857 Hz), 5.95(s, 2H), 5.59 (s, 2H), 3.59 (t, 2H, J=8.17 Hz), 0.91 (t, 2H, J=8.33 Hz),0.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 148.3, 147.6, 146.4, 143.4,143.0, 132.0, 130.8, 122.0, 121.7, 118.8, 116.5, 113.1, 108.5, 105.5,101.3, 92.9, 77.6, 66.3, 17.9, −1.3; LCMS (ESI) [M+H]/z Calc'd 410,found 410.

3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-ylaminewas converted to{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-(3-nitro-phenyl)-amineas described in Example 11, step (v). ¹³C NMR (75 MHz, CDCl₃) δ 150.8,149.7, 149.1, 146.0, 144.8, 143.6, 142.1, 133.1, 132.7, 131.6, 124.0,123.8, 123.1, 120.4, 119.5, 117.2, 116.8, 112.6, 109.9, 106.9, 102.6,99.7, 79.1, 67.9, 19.2, 0.0; MS (FAB) [M+H]/z Calc'd 531, found 531.Anal. Calc'd: C, 63.38; H, 5.70; N, 10.56. Found: C, 63.49; H, 5.76; N,10.42.

{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolyl-6-yl}-(3-nitro-phenyl)aminewas converted to{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methyl(3-nitro-phenyl)-amineas described in Example 11, step (vi). FTIR (KBr) 2952, 2894, 1612,1529, 1503, 1489, 1446, 1407, 1348, 1306, 1251, 1077, 1039 cm−1; ¹³C NMR(75 MHz, CDCl₃) δ 150.1, 149.5, 148.4, 147.8, 147.0, 143.5, 142.4,131.8, 131.5, 129.8, 123.0, 122.49, 121.9, 120.1, 119.5, 118.2, 114.3,11.3, 108.7, 105.7, 104.5, 101.4, 78.0, 66.8, 41.0, 17.9, −1.2; MS (FAB)[M+H]/z Calc'd 545, found 545. Anal. Calc'd: C, 63.95; H, 5.92; N.10.29. Found: C, 62.63; H, 5.72; N, 9.62.

{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methyl-(3-nitro-phenyl)-aminewas converted to[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)1H-indazol-6-yl]-methyl-(3-nitro-phenyl)-amineas described in Example 11. LCMS (EST) [M+H]/z Calc'd 415, found 415.Anal. Calc'd: C, 66.66; H, 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N,13.35.

Example 16(a)N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide

N-[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-N-methyl-benzene-1,3-diamine(prepared as described in Example 15) was converted toN-(3-{[32-benzo[1,3]dioxol-5-yl-vinyl)1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamidein the manner described in Example 12(a). LCMS (ESI) [M+H]/z Calc'd 489,Found 489. Anal. Calc'd: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19;H, 5.09; N, 11.20.

Example 16(b)N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-methyl-benzamide

Example 16(b) was prepared in a similar manner to that described forExample 16(a) above, except that m-toluyl chloride was used instead ofbenzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 504, found 504. Anal.Calc'd: C, 74.09; H, 5.21; N, 11.15. Found: C, 73.04; H, 5.84; N, 10.29.

Example 16(c)N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-dimethylamino-benzamide

Example 16(c) was prepared in a similar manner to that described forExample 16(a), except that m-dimethylaminobenzoyl chloride was usedinstead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 532, found 532.Anal. Calc'd: C, 72.30; H, 550; N, 13.17. Found: C, 71.61; H, 5.80; N,12.75.

Example 16(d)N-(3-{[3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-3-trifluoromethyl-benzamide

Example 16(d) was prepared in a similar manner to that described forExample 16(a), except that m-trifluoromethylbenzoyl chloride was usedinstead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 557, found 557.Anal. Calc'd: C, 66.90; H, 4.17; N, 10.07. Found: C, 66.64; H, 4.34; N,9.82.

Example 16(e)3-Acetyl-N-(3-{[3-(2-benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-amino}-phenyl)-benzamide

Example 16(e) was prepared in a similar manner to that described forExample 16(a), except that m-acetylbenzoyl chloride was used instead ofbenzoyl chloride. LCMS (ESI) [M+H]/z Calc'd 531, found 531. Anal.Calc'd: C, 72.44; H, 4.94; N, 10.56. Found: C, 55.51; H, 4.21; N, 7.58.

Example 16(f)6-[N-(3-(4-tert-butyl-3-hydroxybenzamido)phenyl)-N-methylamino]-3-E-[(3,4-methylenedioxyphenyl)ethenyl]-1H-indazole

Example 16(f) was prepared in a similar manner to that described forExample 16(a), except that 3-tert-butyl-4-hydroxy-benzoic acid, HATU,and TEA were used instead of benzoyl chloride. ¹H NMR (300 MHz, CD₃OD) δ7.90 (d, 1H, J=8.91 Hz), 7.83 (d, 1H, J=2.29 Hz), 7.63 (dd, 1H, J=8.36Hz, J=2.31 Hz), 7.54 (t, 1H, J=1.97 Hz), 7.25-7.43 (m, 4H), 7.14-7.20(m, 2H), 7.06 (dd, 1H, J=8.11 Hz, J=1.55 Hz), 6.96 (dd, 1H, J=8.93 Hz,1=1.97 Hz), 6.90 (m, 1H), 6.82 (t, 2H, J=8.18 Hz), 6.0 (s, 2H), 3.41 (s,3H), 1.42 (s, 9H).

Example 17 Phenyl-(3-styryl-1H-indazol-6-yl)-methanone

Phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanonewas converted to phenyl-(3-styryl-1H-indazol-6-yl)-methanone asdescribed in Example 11 (30 mg, 78%). MS (ESI) [M+H]/z Calc'd 325, found325. Anal. Calc'd: C, 81.46; H, 4.97; N, 8.46. Found: C, 80.36; H, 5.16;N, 8.51.

The starting material was prepared as follows:

To a solution of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole,prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL)cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF(0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction wasquenched with saturated NH₄Cl (aq) and diluted with EtOAc (10 mL) andH₂O (3 mL). The phases were separated and the aqueous was extracted 2×10mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried withNa₂SO₄, decanted and concentrated under reduced pressure. The crudemixture was purified by silica gel chromatography (eluting withhexane:EtOAc 4:1) to givephenyl-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl1-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p=0.39 (7:3 hexane:EtOAc);FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249,1216, 1078, 960, 859, 835 cm¹. MS (ESI) [M+H]/z Calc'd 457, found 457.

To a solution ofphenyl-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol(68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under anatmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg,0.45 mmol). The resulting mixture was stirred at 23° C. for 1 hour. Thesolution was then diluted with hexane (3 mL) then filtered throughCelite and concentrated under reduced pressure to a solid. The crudemixture was purified by silica gel chromatography (eluting withhexane:EtOAc 9:1) to givephenyl-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl]-methanone(54 mg, 79% yield). Rf sm=0.41, Rf p=0.63 (7:3 hexane:EtOAc); FTIR (thinfilm) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649cm⁻¹. MS (ESI) [M+H]/z Calc'd 455, found 455.

Example 18 (3-Amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanone

(3-Amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl}-methanonewas converted to (3-amino-phenyl)(3-styryl-1H-indazol-6 yl)-methanone asdescribed in Example 11. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (dd, 1H, J=0.71,8.50 Hz), 7.91 (s, 1H), 7.64 (dd, 1H, J=1.35, 8.48 Hz), 7.54-7.60 (m,2H), 7.46 (d, 2H, J=12.84 Hz), 7.35-7.40 (m, 2H), 7.22-7.31 (m, 2H),7.16-7.13 (m, 2H), 6.91 (ddd, 1H, J=1.08, 7.89 Hz). LCMS (ESI) [M+H]/zCalc'd 340, found 340.

The starting material was prepared as follows:

6-Iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole wasconverted to(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]1H-indazol-6-yl}-methanolas described in Example 17, step (i). Rf sm=0.71, Rf p=0.25 (7:3hexane:EtOAc); FTIR (thin film) 3369, 3061, 2952, 2894, 2361, 1620,1578, 1530, 1478, 1449, 1350, 1308, 1249, 1215, 1080, 961, 859 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 835 (s, 1H), 8.14 (dd, 1H, J=1.34, 8.14 Hz), 7.99(d, 1H, J=8.38 Hz), 7.76 (d, 1H, J=7.72 Hz), 7.68 (s, 1H), 7.59-7.30 (m,8H), 7.21 (d, 1H, J=8.33 Hz), 6.09 (s, 1H), 5.73 (s, 2H), 3.61 (t, 2H,J=8.30 Hz), 090 (t, 2H, J=8.30 Hz), −0.06 (s, 9H). ¹³C NMR (75 MHz,CDCl₃) δ 148.5, 145.9, 143.4, 142.4, 141.3, 137.1, 132.7, 132.0, 129.5,128.9, 128.2, 126.7, 122.6, 122.6, 121.8, 121.5, 120.8, 119.6, 107.8,77.7, 75.4, 66.8, 17.8, −1.3. Anal. Calc'd: C, 67.04; H, 6.23; N, 8.38.Found: C, 66.93; H, 6.20; N, 8.41.

(3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanolwas converted to (3-nitro-phenyl)-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl)-methanone as described in Example 17,step (ii) (129 mg, 91%). Rf sm=0.46, Rf p=0.23 (7:3 hexane:EtOAc); FTIR(thin film) 3082, 2952, 2894, 1665, 1613, 1532, 1476, 1349, 1298, 1250,1080, 836, 718 cm⁻¹; LCMS (ESI) [M+H]/z Calc'd. 500, found 500.

(3-Nitrophenyl)(3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl)-methanonewas converted to (3-amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazol-6-yl}-methanone as described in Example 11,step (iv) (102 mg, 84%). LCMS (ESI) [M+H]/z Calc'd 340, found 340.

Example 19(a) N-[3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-acetamide

(3-Amino-phenyl)-(3-styryl-1H-indazol-6-yl)-methanone, prepared inExample 18, was converted toN-[3-(3-styryl-1H-indazole-6-carbonyl)-phenyl]-acetamide as described inExample 12(a) (12.2 mg, 78%). Rf sm=0.16, Rf p=0.35 (8:2 CH ₂Cl₂:EtOAc);LCMS (ESI) [M+H]/z Calc'd 382, found 382. Anal. Calc'd: C, 75.57; H,5.02; N. 11.02. Found: C, 74.32; H, 5.41; N, 10.54.

Example 19(b) N-[3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-benzamide

Example 19(b) was prepared in a similar manner to that described forExample 19(a), except that benzoyl chloride was used instead of aceticanhydride. ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.02 (d, 1H, J=8.49Hz), 7.98 (d, 1H, J=1.01 Hz), 7.95 (s, 1H), 7.95 (s, 1H), 7.83-7.88 (m,3H), 7.65 (dd, 1H, J=1.04, 8.48 Hz), 7.29-7.56 (m, 11 H). MS (ESI)[M+H]/z Calc'd 444, found 444. Anal. Calc'd: C, 78.54; H, 4.77; N, 9.47.Found: C, 78.01; H, 4.87; N, 9.32.

Example 19(c) [3-(3-Styryl-1H-indazole-6-carbonyl)-phenyl]-carbamic acidbenzyl ester

The title compound was prepared in a similar manner to that describedfor Example 19(a), except that carboxybenzyloxy chloride was usedinstead of acetic anhydride. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (d, 1H,J=8.48 Hz), 7.98 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H,J=7.44 Hz), 7.61 (d, 2H, J=1.81 Hz), 7.58 (s, 1H), 7.51 (t, 1H, J=7.79Hz), 7.42 (t, 5H, J=6.56 Hz), 7.31-7.37 (m, 4H), 5.16 (s, 2H); LCMS(ESI) [M+H]/z Calc'd 474, found 474. Anal. Calc'd: C, 76.09; H, 4.90; N,8.87. Found: C, 73.82; H. 4.93; N, 8.27.

Example 19(d) 5-Methyl-thiazole-2-carboxylic acid[3-(3-styryl-1H-indazole-6-carbonyl)phenyl]-amide

(3-Amino-phenyl)(3-styryl-H-indazol-6-yl)-methanone was converted to5-methyl-thiazole-2-carboxylic acid[3-(3-styryl-H-indazole-6-carbonyl)-phenyl]-amide as described inExample 12(d) (9.9 mg, 28%). ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, 1H,J=8.49 Hz), 8.09 (t. 1H, J=1.86 Hz), 8.04 (dd, 1H, J=1.0, 7.98 Hz), 7.99(s, 1H), 7.75 (dd, 1H. J=1.31, 8.47 Hz), 7.67 (s, 1H), 7.63 (d, 2H,J=7.30 Hz), 7.54-7.58 (m, 3H), 7.50 (s, 1H), 7.42 (t, 3H, J=8.09 Hz);LCMS (ESI) [M+H]/z Calc'd 465, found 465.

Example 19(e)6-[3-(5-methylpyridin-3-ylcarboxamido)benzoyl]-E-styryl-1H-indazole

Example 19(e) was prepared in a similar manner to Example 19(d) exceptthat 5-methyl-nicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s,1H), 8.99 (d, 1H, J=0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H,J=8.32 Hz), 2.97 (dd, 1H, J=8.3 Hz, J=0.94 Hz), 7.72 (d, 1H, J 5=16.65Hz), 7.64 (d, 2H, J=7.21 Hz), 7.19-7.47 (m, 8H), 6.95 (d, 1H, J=6.43Hz), 2.49 (s, 3H). MS (ESI+) [M+H]/z Calc'd 459, found 459. Anal.Calc'd: C, 75.97. H, 4.84. N, 12.22. Found: C, 75.86. H, 4.94. N, 12.10.

Example 19(f)6-[3-(indol-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(f) was prepared in a similar manner to Example 19 (d) except1H-Indole-4-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. LCMS (ESI+) [M+H]/z Calc'd 483,found 483. Anal. Calc'd: C, 77.16; H, 4.60; N, 11.61. Found: C, 76.15;H, 4.49; N, 11.31.

Example 19(g)6-[3-(pyridin-2-ylacetamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(g) was prepared in a similar manner to Example 19(d), exceptthat, pyridin-2-yl-acetic acid was used instead. ¹H NMR (300 MHz, CDCl₃)δ 8.50 (dd, 1H, J=4.86 Hz, 3=0.91 Hz), 8.37 (d, 1H, J=8.51 Hz), 8.09 (s,1H), 7.94 (d, 1H, J=7.89 Hz), 7.87 (s, 1H), 7.73-7.79 (m, 3H), 7.25-7.60(m, 10H) 3.86 (s, 2H). MS (ESI) [M+H]/z Calc'd 459, found 459. Anal.Calc'd: C, 75.97. H, 4.84. N, 12.22. Found: C, 74.70. H, 4.83. N, 11.99.

Example 19(h) 6-[3-(2-methylpropionamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(h) was prepared in a similar manner to Example 19(a).Isobutyryl chloride was used instead of acetyl chloride. ¹H NMR (300MHz, DMSO-d₆) δ 8.38 (d, 1H, J=8.13 Hz), 8.08 (t, 1H), 7.96 (s, H. J=7.8Hz, J=1.91 Hz), 7.88 (s, 1H), 7.75 (d, 2H, J=7.25 Hz), 7.61 (d, 2H, 2.05Hz), 7.40-7.58 (m, 5H), 7.31 (m, 1H), 2.60 (m, 1H, 1=6.82 Hz), 1.1 (d,6H, J=6.82 Hz). (MS (ESI+) [M+Na]/z Calc'd 432, found 432. Anal. Calc'd:C, 76.26. H, 5.66. N, 10.26. Found: C, 75.14. H, 5.62. N, 10.08.

Example 19(i)6[3-(2-acetamido-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(i) was prepared in a similar manner to Example 19(d) exceptthat acetylamino-2-phenyl-acetic acid was used instead of5-methyl-thiazole-2-carboxylic acid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.5(s, 1H), 10.6 (s, 1H), 8.66 (d, 1H, J=7.66 Hz), 8.36 (d, 1H, 3=8.47 Hz),8.07 (s, 1H), 7.92 (d, 1H, J=7.63 Hz), 7.86 (s, 1H), 7.75 (d, 2H, J=7.33Hz), 7.29-7.60 (m, 13H), 5.61 (d, 1H, J=7.6 Hz), 1.92 (s, 3H). LCMS(ESI+) [M+H]/z Calc'd 515, found 515. Anal. Calc'd: C, 74.69. H, 5.09.N, 10.89. Found: C, 73.01. H. 5.01. N, 10.60.

Example 19(j)6-[3-(pyridin-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(j) was prepared in a similar manner to Example 19(d) exceptthat isonicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc'd 467,found 467. Anal. Calc'd: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17;H, 4.62; N, 12.31.

Example 19(k)6-[3-(pyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(k) was prepared in a similar manner to Example 19(d) exceptthat pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc'd 467,found 467. Anal. Calc'd: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17;H, 4.61; N, 12.44.

Example 19(l)6-[3-(isoxazol-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(l) was prepared in a similar manner to Example 19(d) exceptthat isoxazole-5-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 435, found435. Anal. Calc'd: C, 71.88; H, 4.18; N, 12.90. Found: C, 71.36; H,4.33; N, 12.47.

Example 19(m)6-[3-(6-chloropyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(m) was prepared in a similar manner to Example 19(d) exceptthat 6-chloro-pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+Nay/z Calc'd 501,found 501.

Example 19(n)6-[3-(4-chloropyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(n) was prepared in a similar manner to Example 19(d) except4-, chloro-pyridine-2-carboxylic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 479, found479. Anal. Calc'd: C, 70.22; H, 4.00; N, 11.70. Found: C, 70.07; H,4.09; N, 11.64.

Example 19(o)6-[3-(2-chloropyridin-4-ylcarboxamido)benzoyl]-3-E-styryl-1H-indazole

Example 19(o) was prepared in a similar manner to Example 19(d) except2-chloro-isonicotinic acid was used instead of5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc'd 479, found479.

Example 19(p)6-[3-(2-methylamino-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole

To a solution of6[3-(2-(N-t-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazole(115 mg, 0.2 mmol) in CH₂Cl₂ (2 ml) cooled to 0° C. was added TFA (2ml). After 40 min. the reaction mixture was quenched with saturatedNaHCO₃ (aq), then extracted with CH₂Cl₂ (2×10 ml). The Organics werewashed with brine, dried with Na₂SO₄, decanted and concentrated.Purification by silica gel chromatography (1:10methanol-dichloromethane) gave6[3-(2-methylamino-2-phenylacetamido)benzoyl]-3-E-styryl-1H-indazole (38mg, 39%). MS (ESI+) [M+H]/z Calc'd 487, found 487. Anal. Calc'd: C,76.52; H, 5.39; N, 11.51. Found: C, 74.99; H, 5.76; N, 10.89.

The starting material was prepared as described below:

-   -   (i)        6[3-(2-(N-1-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazole        6-[3-(2-(N-t-butoxycarbonyl-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-E-styryl-1H-indazole        was prepared in a similar manner to Example 19(d) except that        (t-butoxycarbonyl-methyl-amino)-phenyl-acetic acid was used        instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI+)        [M+H]/z Calc'd 587, found 587.

Example 20(a) 6-(3-Acetamido-phenylsulfanyl)-3-styryl-1H-indazole

6-(3-Acetamido-phenylsulfanyl)₃-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to 6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole asdescribed in Example 11 (30 mg, 81%): R_(f) sm 0.65, p 0.35 (10%methanol in dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, 1H,J=8.5 Hz), 7.59 (bs, 1H), 7.48-7.0 (m. 13H), 1.98 (s, 3H); HRMS (FAB)[M+Na]/z Calc'd 408.1147, found 408.1156.The starting material was prepared as follows:

To the 9-BBN adduct of 3-phthalamido-thiophenol (1.4 equiv), which wasprepared in situ as described below, was added3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (250 mg,0.5 mmol), Pd(dppf)Cl₂ (87 mg, 0.2 equiv) and potassium phosphate (339mg, 1.6 mmol, 3.00 equiv) in DMF (3.0 mL). The reaction mixture washeated to 90° C. for 9 h. The mixture was cooled and partitioned betweenethyl acetate and saturated sodium bicarbonate. The organic material wasdried over sodium sulfate, decanted and concentrated. Purification bysilica gel chromatography (2:8 ethyl acetate-hexane) gave6-(3-phthalamido-phenylsulfanyl)-3-iodo-1H-indazole as an oil (159 mg,50%): ¹H NMR (300 MHz, CDCl₃) δ 7.93 (m, 2H), 7.79 (m, 2H), 7.62 (s,1H), 7.5-7.3 (m, 5H), 7.22 (d, 1H), 5.68 (s, 2H), 3.55 (t, 2H, J=8.2Hz), 0.87, (t, 2H, J=8.2 Hz), −0.06 (s, 9H); HRMS (FAB) (M+Cs]/z Calc'd759.9563, found 759.9571.

The boron reagent was prepared as follows: In a 10 mL Schlenk flask3-phthalamido-thiophenol was dried under high vacuum. To this was addeda solution of 9-BBN (0.5 M in THF, 1.6 mL, 1.0 equiv). The mixture washeated to 55° C. for 2 h. The volatile material was removed under astream of argon at 70° C. for 1.5 h. The residue was used withoutfurther manipulation.

6-(3-Phthalamido-phenylsulfanyl)-3-iodo-1H-indazole was converted to6-(3-phthalamido-phenylsulfanyl)-3-styryl-1H-indazole as described inExample 11, step (iii). ¹H NMR (300 MHz, CDCl₃) δ 7.93 (m, 3H), 7.78 (m2H), 7.7 (s, 1H), 7.58 (m, 2H), 7.47-7.26 (m, 10H), 5.71 (s, 2H), 3.59(t, 2H, J=8.2 Hz), 0.89 (t, 2H, J=8.2 Hz), −0.06 (s, 9H); HRMS (FAB)[M+Cs]/z Calc'd 736.1066, found 736.1058.

To a solution of 6-(3-phthalamidophenylsulfanyl)-3-styryl-1H-indazole(121 mg, 0.2 mmol) in ethanol (3.5 mL) was added hydrazine (63 μL, 2.0mmol, 10 equiv). The reaction mixture was allowed to stir at 23° C. for45 min and was diluted with saturated sodium bicarbonate and ethylacetate. The organic material was dried over sodium sulfate, decantedand concentrated. Purification by silica gel chromatography (3:7 ethylacetate-hexane) gave 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole asan oil (79 mg, 90%): ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, 1H, J=8.5 Hz),7.57 (m, 3H), 7.49 (d, 1H, J=16.8 Hz), 7.4-7.25 (m, 4H), 7.23 (dd, 1H,J=1.5, 8.5 Hz), 7.11 (t, 1H, J=7.9 Hz), 6.79 (m, 1H), 6.70 (t, 1H, J=1.9Hz), 6.59 (m, 1H), 5.66 (s, 2H), 3.60 (bs, 2H), 3.59 (t, 2H, J=8.2 Hz),0.90 (t, 2H, J=8.2 Hz), −0.05 (s, 9H); HRMS (FAB) [M+H]/z Calc'd474.2035, found 474.2019.

To a solution of 6-(3-aminophenylsulfanyl)-3-styryl-1H-indazole (43.7mg, 0.10 mmol) in dichloromethane (0.5 mL) was added pyridine (81 μL,1.0 mmol, 10 equiv), and acetic anhydride (47 μL 0.5 mmol, 5 equiv). Themixture was allowed to stir for 10 min at 23° C. The mixture was dilutedwith water and the product was extracted with 30% hexane in ethylacetate. The organic material was washed with 5% citric acid andsaturated sodium bicarbonate. The organic material was dried over sodiumsulfate, decanted and concentrated. Purification by silica gelchromatography (3:7 ethyl acetate-hexane) gave6-(3-acetamido-phenylsulfanyl)-3-styryl-1H-indazole as an oil (50 mg,97%): R_(f) sm 0.33, Rf p 0.18 (ethyl acetate-hexane 3:7); ¹H NMR (300MHz, CDCl₃) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t,2H, J=8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). HRMS(FAB) [M+Cs]/z Calc'd 648.1117, found 648.1098.

Example 20(b) 6-(3-(Benzoylamido)-phenylsulfanyl)-3-styryl-1H-indazole

The title compound was prepared like Example 20(a), except that benzoylchloride was used instead of acetic anhydride in step (iv). ¹H NMR (300MHz, CDCl₃) δ 8.03 (s, 1H), 7.73 (d, 1H, J=8.5 Hz), 7.63 (m, 2H), 7.47(m, 1H), 7.42 (t, 1H, J=1.9 Hz), 7.37 (m, 3H), 7.31 (m, 1H), 7.28-6.98(m, 9H); HRMS (FAB) [M+H]/z Calc'd 448.1484, found 448.1490.

Example 21 6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1H-indazole

6-(1-(3-Aminophenyl)vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]1H-indazole was converted to the tide compound as described for Example11 (85 mg, 85%): R_(f) sm 0.72, p 0.37 (ethyl acetate-hexane 1:1); FTIR(thin film) 3385, 3169, 2953, 1621, 1581, 1489, 1447, 1349, 1251, 1165,1071, 959, 906, 870, 817 cm⁻¹; ¹H NM (300 MHz, CDCl₃) δ 7.98 (d, 1H.J=8.5 Hz), 7.60 (m, 2H), 751 (s, 1H), 7.48 (s, 1H), 7.40 (m, 3H), 7.29(m, 2H), 7.15 (m, 1H), 6.78 (m, 1H), 6.68 (m, 2H), 5.50 (s, 2H), 3.65(bs, 2H); MS (ES) [M+H]/z Calc'd 338, found 338; MS (ES) [M−H]/z Calc'd336, found 336.

The starting material was prepared as follows:

To a solution of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole,prepared in Example 14, step (i), (330 mg, 0.693 mmol) in THF (3.0 mL)at −78° C. was added n-butyllithium (0.56 mL, 1.5 M, 1.2 equiv). After20 min, this solution was then added to anhydrous zinc chloride (170 mg)and the mixture was warmed to 23° C. and stirred for 15 min. To thismixture was added 1-(3-nitro-phenyl)vinyltriflate (146 μL, 1.05 equiv)and Pd(PPh₃)₄ (40 mg, 0.05 equiv). This mixture was stirred for 30 min,was partitioned between ethyl acetate and saturated sodium bicarbonateand the organic layer was separated. The organic material was dried oversodium sulfate, decanted and concentrated under reduced pressure.Purification by silica gel chromatography (1:9 ethyl acetate-hexane)then a second column (1% ethyl acetate/benzene) gave6-(1-(3-nitrophenyl)vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleas an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448,1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 8.26 (t, 1H, J=1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, J=8.5 Hz),7.69 (dt, 1H, J=1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, 1H, J=1.4, 8.4Hz), 5.72 (s, 3H), 5.69 (s, 1H), 3.60 (t, 2H, J=8.2 Hz), 0.89 (t, 2H,J=8.2 Hz), −0.05 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 149.9, 149.6, 144.7,144.5, 142.8, 140.7, 138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0,124.4, 124.2, 124.1, 123.8, 122.6, 121.2, 118.9, 111.0, 79.2, 68.0,19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 520.2031, found 520.2046.

6-(1-(3-Nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas converted to6-(1-(3-aminophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazoleas described in Example 11, step (iv) (140 mg, 95%): R_(f) sm 0.59, p0.46 (ethyl acetate-hexane 4:6); FTIR (thin film) 3460, 3366, 3223,3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448,1359.1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.96 (d, 1H, J=8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H),7.46 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H),6.77 (m, 1H), 6.68 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 151.6, 147.7,144.6, 143.9, 142.8, 142.4, 138.6, 132.8, 130.6, 130.2, 129.3, 128.0,124.4, 123.6, 121.9, 121.5, 120.2, 116.4, 116.1, 110.8, 79.0, 67.9,19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 490.2291, found 490.2302.

Example 22(a)6-(1-(3-(5-Methyl-thiaxole-2-carboxoylamido)phenyl)-vinyl)-3-styryl-1N-indazole

6-(1-(3-Aminophenyl)vinyl)-3-styryl-1H-indazole was converted to thetitle compound as described in Example 12(d) (20 mg, 72%): FTIR (thinfilm) 3271, 1673, 1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090, 960,907, 871 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 10.7 (bs, 1H), 9.09 (s, 1H),8.0 (d, 1H), 7.79 (m, 1H), 7.60 (m, 3H), 7.51 (m, 3H), 7.44-7.15 (m,7H), 5.59 (s, 2H), 254 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.2, 157.9,149.8, 144.4, 142.8, 142.2, 141.9, 141.5, 140.6, 137.63, 137.56, 131.6,129.5, 129.1, 128.3, 126.9, 125.1, 122.6, 121.2, 120.9, 120.5, 120.2,119.8, 116.1, 110.2, 12.8; HRMS (FAB) [M+H]/z Calc'd 463.1593, found463,1582.

Example 22(b) 6-(1-(3-(Benzoylamido)phenyl)-vinyl)-3-styryl-1H-indazole

Example 22(b) was prepared in a similar manner to that described forExample 22(a), except that benzoyl chloride was used instead of5-methyl-thiazole-2-carboxylic acid and HATU. FTIR (thin film) 3243,1651, 1606, 1580, 1538, 1485, 1447, 1428, 1349, 1307, 1258, 1073, 959,907 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 7.99 (d, 1H, J=8.5Hz), 7.78 (m, 1H), 7.60 (m, 3H), 7.51 (m, 3H), 7.43-7.15 (m, 10H), 556(d, 2H, J=3.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 149.7, 144.3, 142.7,142.1, 140.6, 138.1, 137.6, 135.0, 132.3, 131.6, 129.4, 129.1, 128.3,127.4, 126.9, 125.0, 122.5, 120.9, 120.8, 120.6, 120.5, 115.9, 110.2;HRMS (FAB) [M+H]/z Calc'd 442.1919, found 442.1919.

Example 22(c) 6-(1-(3-Benzoylamido)phenyl)-vinyl)-3-styryl-1H-indazole

The title compound was prepared in a similar manner to that describedfor Example 22(a), except that carbobenzyloxy chloride was used insteadof 5-methyl-thiazole-2-carboxylic acid and HATU. FTIR (thin film) 3305,1712, 1606, 1586, 1537, 1487, 1445, 1348, 1216, 1059, 959, 908 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.99 (d, 1H, J=8.5 Hz), 7.6-7.0 (m, 18H), 5.55(s, 2H), 5.19 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 153.9, 149.8, 144.3,142.7, 142.1, 140.7, 138.2, 137.6, 136.3, 131.7.129.4, 129.1, 129.0,128.7, 128.7, 128.3, 126.9, 124.0, 122.6, 121.1, 120.8, 120.4, 115.9,110.1, 67.4; HRMS (FAB) [M+H]/z Calc'd 472.025, found 472.2026.

Example 23 6-(1-(3-Acetamidophenyl)-vinyl)-3-styryl-1H-indazole

6-(1-(3-Acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazolewas converted to 6-(1-(3-acetamido-phenyl)vinyl)-3-styryl-1H-indazole asdescribed for Example 11: FTIR (thin film) 3252, 1667, 1606, 1557, 1486cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 10.4 (bs, 1H), 7.91 (d, 1H, J=8.5 Hz),7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s, 3H); MS (ES) [M+H]/z Calc'd380, found 380; [M−H]/z Calc'd 378, found 378.

The starting material was prepared as follows:

6-(1-(3-Aminophenyl)-vinyl)-3-styryl1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazole was converted to6-(1-(3-acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazoleas described for Example 12(a): R_(f) sm 0.42, p 0.26 (ethylacetate-hexane 4:6); FTIR (thin film) 3305, 3059, 2952, 1667, 1608,1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836,748, 693 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, 1H, J=8.5 Hz), 7.7-7.4(m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J=1.3, 8.4 Hz), 7.16 (bd, 1H, J=7.8Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, J=8.2 Hz),2.16 (s, 3H), 0.98 (t, 2H, J=8.2 Hz), −0.02 (s, 9H); ¹³C NMR (75 MHz,CDCl₃) δ 169.8, 150.9, 144.6, 143.5, 142.8, 142.0, 139.4, 138.6, 132.9,130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3, 121.0, 117.1,110.8, 68.0, 25.8, 19.1, 0.0; HRMS (FAB) [M+Na]/z Calc'd 532.2396, found532.2410.

Example 24(a)4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-2-methoxy-5-methyl-phenol

6-{5-Methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(triethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazole(326 mg, 0.43 mmol) was stirred in a solution of TBAF (4.5 mL of 1 M inTHF, which was concentrated in vacuo to 2.5 mL) and ethylenediamine (0.6mL, 8.9 mmol) at reflux for 40 h. The reaction was diluted with ethylacetate/THF (40 mL/5 mL) and washed with H₂O (20 mL) and brine (20 mL).Organics were dried (MgSO₄) and concentrated in vacuo. Purification bysilica gel chromatography (60% THF/hexanes) and then precipitation fromchloroform gave 108 mg (68%) of4-[3-(1-H-benzoimidazol-2-yl)-1-H-indazol-4-yl]-2-methoxy-5-methyl-phenolas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.62 (s, 1H), 13.05 (brs, 1H), 9.01 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.62 (br s, 2H), 7.49 (s.1H), 7.28-7.20 (m, 3H), 6.85 (s, 1H), 6.74 (s, 1 H), 3.77 (s, 3H), 2.15(s, 3H). Anal. (C₂₂H₁₈N₄O₂ 1.3H₂O)C, H, N. Calculated: C, 67.10; H,5.27; N, 14.23. Found: C, 67.30; H, 5.27; N, 14.11.

The starting materials were prepared as follows:

Preparation of2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole. Asolution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole(5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51, 1891-1894(1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12min via cannula to a flask containing n-butyllithium (2.5 M in hexanes,12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25min at −78° C., the flask was warmed to 0° C. for 10 min, then cooledagain to −78° C. This solution was then added via cannula to a secondflask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C.Once the addition was complete (−5 min), the cooling bath was removed,and stirring was continued for 30 min. The reaction mixture waspartitioned between ethyl acetate (500 mL) and water (100 mL). Theorganic layer was washed with saturated aqueous sodium metabisulfite(2×100 mL) to remove the dark iodine color, dried (MgSO₄), andconcentrated in vacuo. Purification by flash chromatography (10% to 50%ethyl acetate/hexanes) yielded 4.79 g (63%) of pure2-iodo-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-benzoimidazole as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m,1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t,2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C₁₃H₁₉IN₂OS)C, H. Calculated: C,41.71; H, 5.12; L 33.90; N, 7.48. Found: C, 41.90; H, 5.09; L 34.00; N,7.37.

Preparation of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole:3-Iodo-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-indazole (10.0g, 23.9 mmol) and hexamethylditin (10.0 g, 30.5 mmol) were combined withdry toluene (45 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)-palladium(0) (300 mg, 0.26 mmol) was added,and the reaction stirred at reflux under argon for 2.5 h. The reactionwas cooled to 23° C. and diluted with ether (60 mL). Organics werewashed with 0.1N HCl (20 mL) and brine (20 mL), dried (MgSO₄), andconcentrated. Purification by silica gel chromatography (3% to 8%ether/hexanes) gave 7.70 g (71%) of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazoleas a faintly yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, 1H, J=1.8Hz), 8.03 (dd, 1H, J=8.7, 1.8 Hz), 7.81 (d, 1H, J=8.7 Hz), 5.84 (s, 2H),3.58 (t, 2H, J=8.1 Hz), 0.90 (t, 2H, J=8.1 Hz), 0.50 (t, 9H, J=28.2 Hz),−0.05 (s, 9H). Anal. (C₁₆H₂₇N₃O₃SiSn) C, H, N. Calculated: C, 42.13; H,5.97; N, 9.21. Found: C, 42.39; H, 6.01; N, 9.26.

Preparation of6-nitro-1-[2-(trimethyl-silanyl)ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole(7.50 g, 16.4 mmol),3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g,17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined withdry THF (150 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) was added, and the reactionstirred at reflux under argon for 23 h. The reaction was cooled andadsorbed directly onto silica gel (−16 g). Purification by silica gelchromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a light yellow solid. ¹H NMR (300 MHz, CDCl₃) a 8.91 (d, 1H, J=9.0Hz), 8.59 (d, 1H, J=1.8 Hz), 8.22 (dd, 1H, J=8.7, 1.8 Hz), 7.92-7.89 (m,1H), 7.667.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H),3.68-3.59 (m, 4H), 0.94 (t, 2H, J=8.1 Hz), 0.86 (t, 2H, J=8.1 Hz), −0.04(s, 9H), −0.15 (s, 9H). Anal. (C₂₆H₃₇N₅O₄Si₂) C, H. N. Calculated: C,57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.

Preparation of6-Amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:Tin(II) chloride (12.0 g, 63.3 mmol) was added to a solution of6-nitro-1-[2-(trimethyl-silanyl)ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(7.18 g, 13.3 mmol) in DMF/H₂O (160 mL/10 mL), and the reaction stirredat 50° C. for 2.5 h. The reaction was cooled to 0° C., and saturatedsodium bicarbonate was added slowly, with mixing, until all frothingfrom quenching had subsided. The material was concentrated in vacuo andtaken up in ether (100 mL). Insoluble material was removed by filtrationand rinsed with ether (50 mL). The filtrate was washed with brine (50mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silicagel chromatography (25% ethyl acetate/hexane) gave 6.05 g (89%) of6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a faintly yellow waxy solid. ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, 1H,J=9.0 Hz), 7.89-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.31 (m, 2H), 6.78(dd, 1H, J=8.7, 1.8 Hz), 6.75 (s, 1H), 6.25 (s, 2H), 5.69 (s, 2H), 3.93(br s, 2H), 3.65-355 (m, 4H), 0.93 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.1Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C₂₆H₃₉N₅O₂Si₂) C, H, N.Calculated: C, 61.26; H, 7.71; N. 13.74. Found: C, 61.18; H, 7.65; N,13.82.

Preparation of6-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole:A solution of6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(500 mg, 0.98 mmol) in acetic acid (1.5 mL) was diluted with H₂O (1.0mL) and stirred at 0° C. Concentrated HCl (250 e”-3 mmol) in H₂O (250μL) was added. Sodium nitrate (90 mg, 1.3 mmol) in H₂O (300 μl) wasadded, and the reaction stirred for 8 min. Iodine (10 mg) and a solutionof potassium iodide (250 mg, 1.3 mmol) in H₂O (250 μL) were added, andthe frothing reaction stirred for 30 min at 23° C. The reaction wasdiluted with H₂O (25 mL) and extracted with ethyl acetate (2×20 mL).Organics were washed with saturated sodium metabisulfite solution (10mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo.Purification by silica gel chromatography (8% ethyl acetate/hexanes)gave 316 mg (52%) of6-iodo-1-[2-(trimethyl-silanyl)ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazoleas a faintly yellow oil, which slowly crystallized to a white solid. ¹HNMR (300 MHz, CDCl₃) δ 8.45 (d, 1H, J=9.0 Hz), 8.05 (s, 1H), 7.91-7.88(m, 1H), 7.67-7.62 (m, 2H), 7.38-7.34 (m, 2H), 6.24 (s, 2H), 5.77 (s,2H), 3.65-3.57 (m, 4H), 0.93 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.1 Hz),−0.04 (s, 9H), −0.15 (s, 9H). Anal. (C₂₆H₃₇₁N₄O₂Si₂) C, H, N.Calculated: C, 50.31; H, 6.01; N, 9.03. Found: C, 50.55; H, 6.08; N,9.00.

Preparation of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)ethyl]-trimethyl-silane:4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett.,12, 1351-1352 (1997)) was stirred in dry CH₂Cl₂ (100 mL) at 23° C. DIEA(6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)ethoxymethyl chloride(5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution waswashed with H₂O, 0.1 N HCl, H₂O, saturated NaHCO₃, and brine (25 mLeach). Organics were dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (6% ethyl acetate/hexanes)gave 9.06 g (91%) of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silaneas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.06 (s, 1H), 7.02 (s, 1H),5.24 (s, 2H), 3.84 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 2.31 (s, 3H), 0.96(t, 2H, J=8.4 Hz), 0.01 (s, 9H).

Preparation of5-methoxy-2-methyl-4[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid:[2-(4-Bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane(2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at −78° C. under argon.n-Butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) was addeddropwise, and the reaction stirred for 30 min before it was transferredvia cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15mL), which was also stirring at −78° C. under argon. After addition wascomplete, the reaction stirred 30 min at −78° C. and then 30 min whilewarming to 0° C. It was then quenched with H₂O (20 mL), acidified with0.1 N HCl, and extracted with ethyl acetate (2×25 mL). Organics werewashed with brine (20 mL), dried (Na₂SO₄), and concentrated in vacuo.Purification by silica gel chromatography (20% to 50% ethylacetate/hexanes) gave 1.11 g (47%) of5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.78 (s, 1H), 7.10 (s,1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.83 (t, 2H, J=8.4 Hz), 2.79 (s, 3H),0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C₁₄H₂₅BO₅Si—H₂O)C, H.Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.

Preparation of 6-{5-methoxy-2-methyl[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazole.6-Iodo1-[2-(trimethyl-silanyl)ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole(350 mg, 0.56 mmol),5-methoxy-2-methyl-4[2-(triethyl-silanyl)ethoxymethoxy]-phenyl-boronicacid (211 mg, 0.68 mmol), and sodium carbonate (72 mg, 0.68 mmol) werestirred in a mixture of benzene (5 mL), H₂O (330 μL), and methanol (1mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) was added, and the reactionstirred at reflux under argon for 16 h. After cooling to 23° C., thereaction was diluted with ether (20 mL), washed with H₂O (10 mL) andbrine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. Purificationby silica gel chromatography (15% ethyl acetate/hexanes) gave 382 mg(89%) of6-{5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzamidazol-2-yl}-1-H-indazoleas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1H, J=8.4 Hz),7.93-7.90 (m, 1H), 7.67-7.63 (m, 1H), 7.54 (s, 1H), 7.38-7.32 (m, 3H),7.13 (s, 1H), 6.86 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.34 (s, 2H),3.89 (s, 3H), 3.86 (t. 2H, J=8.4 Hz), 3.69-3.58 (m, 4H), 2.22 (s, 3H),1.01 (t, 2H, J=8.4 Hz), 0.95-0.83 (m. 4H), 0.03 (s, 9H), 0.05 (s, 9H),−0.15 (s, 9H). Anal. (C₄₀H₆₀N₄O₅Si₃) C, H, N. Calculated: C, 63.12; H,7.95; N, 7.36. Found: C, 63.22; H, 7.93; N, 7.46.

Example 24(b)4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-3-methyl-phenol

To prepare the title compound, the procedure described for Example 24(a)was followed, with2-methyl-4-[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid(prepared as described below) substituted for 5-methoxy-2-methyl4[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid in step(viii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 12.99 (br s, 1H),9.41 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.72 (br s, 1H), 7.52 (br s, 1H),7.45 (s, 1H), 7.25-7.21 (m, 3H), 7.12 (d, 1H, J=8.1 Hz), 6.73-6.67 (m,2H), 2.20 (s, 3H). Anal. (C₂₁H16N₄O.0.7H₂O) C, H. N. Calculated: C,71.45; H, 4.97; N, 15.87. Found: C, 71.44; H, 4.96; N, 15.77.

2-Methyl-4[2-(triethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid wasprepared as follows:

[2-(4-Bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane wasprepared in 86% yield from 4-bromo-3-methyl-phenol according to theprocedure for[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane.¹H NMR (300 MHz, CDCl₃) δ 7.39 (d, 1H, J=8.7 Hz), 6.93 (d, 1H, J=2.7Hz), 6.75 (dd, 1H, J=8.7, 2.7 Hz), 5.16 (s, 2H), 3.74 (t, 2H, J=8.4 Hz),2.36 (s, 3H), 0.95 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C₁₃H₂₁BrO₂Si)C, H. Calculated: C, 49.21; H, 6.67. Found: C, 49.33; H. 6.67.

2-Methyl-4[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid wasprepared in 52% yield from[2-(4-bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane accordingto the procedure for 5-methoxy-2-methyl4[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid above. ¹H NMR(300 MHz, CDCl₃) δ 8.15 (d, 1H, J=8.1 Hz), 6.98-6.92 (m, 2H), 5.29 (s,2H), 3.78 (t, 2H, J=8.4 Hz), 2.78 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01(s, 9H). Anal. (C₁₃H₂₃BO₄Si —H₂O)C, H. Calculated: C, 59.10; H, 8.01.Found: C, 59.07; H, 8.08.

Example 24(c)4-[3-(1-H-Benzoimidazol-2-yl)-1-H-indazol-6-yl]-2-chloro-5-methyl-phenol

To prepare the tide compound, 5-chloro-2-methyl-4-[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid, prepared as described below, wassubstituted for5-methoxy-2-methyl-4-[2(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronicacid in the procedure described in Example 24(a), step (viii). ¹H NMR(300 MHz, DMSO-d₆) δ 13.61 (s, 1H), 13.00 (br s, 1H), 10.22 (s, 1H),8.51 (d, 1H, J=8.4 Hz), 7.64 (br s, 2H), 750 (s, 1H), 7.26-7.21 (m, 4H),6.95 (s, 1H), 2.19 (s, 3H).

5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronicacid was prepared as follows:

2-Chloro-5-methyl-phenol (6.68 g, 46.9 mmol) was stirred in acetonitrile(200 mL). N-Bromosuccinimide (8.5 g, 47.8 mmol) was added, and thereaction stirred for 45 min. The solution was concentrated in vacuo andredissolved in chloroform (100 mL). Organics were washed with saturatedNaHCO₃ (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated invacuo. Purification by silica gel chromatography (8% ethylacetate/hexanes) gave 7.98 g (77%) of 4-bromo-3-chloro-5-methyl-phenolas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.47 (s, 1H), 6.91 (s, 1H),5.52 (br s, 1H), 2.32 (s, 3H). Anal. (C₇H₆ClBrO 0.1H₂O)C, H. Calculated:C, 37.66; H. 2.80. Found: C, 37.57; H, 2.82.

[2-(4-Bromo-2-chloro-5-methyl-phenoxymethoxy)ethyl]-trimethyl-silane wasprepared in 83% yield from 4-bromo-3-chloro-5-methyl-phenol according tothe procedure for[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane.¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79(t, 2H, J=8.4 Hz), 2.35 (s, 3H), 0.95 (t, 2H, 3=8.4 Hz), 0.02 (s, 9H).Anal. (C₁₃H₂₀ClBrO₂Si) C, H. Calculated: C, 44.39; H, 5.73. Found: C.45.08; H, 5.91.

5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid was prepared in 54% yield from[2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silaneaccording to the procedure for5-methoxy-2-methyl-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronicacid. ¹H NMR (300 MHz, CDCl₃) δ 8.11 (s. 1H), 7.09 (s, 1H), 5.37 (s,2H), 3.84 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01(s, 9H). Anal. (C₁₃H₂₂BClO₄Si—H₂O)C, H. Calculated: C, 52.28; H, 6.75.Found: C, 51.98; H. 6.84.

Example 24(d)3-1H-Benzoimidazol-2-yl-6-(4-hydroxy-2-methoxyphenyl)-1H-indazole

Example 24(d) was prepared in a similar manner to that described forExample 24(a), except that 4-bromo-3-methoxy-phenol, prepared asdescribed by Carreno et. al., Syn. Let., 11, 124142 (1997), was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹NMR (300MHz, DMSO-d₆) δ 13.52 (s, 1H), 12.98 (s, 1H), 9.63 (s, 1H), 8.44 (d, 1H,J=8.4 Hz), 7.72 (d, 1H, J=6.9 Hz), 7.61 (s, 1H), 7.50 (d, 1H, J=6.9 Hz),7.36(dd, 1H, J=8.4, 1.5 Hz), 7.18-7.22 (m, 3H), 6.55 (d, 1H, J=2.1 Hz),6.48 (dd, 1H, J=8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [m+H]/z calc'd 357,found 357; [m−H]z calc'd 355, found 355.

Example 24(e)3-1H-Benzoimidazol-2-yl-6-(2-ethyl-4-hydroxyphenyl)-1H-indazole

Example 24(e) was prepared in a similar manner to that described forExample 24(a), except that 4-bromo-3-ethyl-phenol, prepared in 80% yieldaccording to the procedure described by Carreno et. al., Syn. Lett., 11,1241-42 (1997) for the synthesis of 4-bromo-3-methyl-phenol, was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300MHz, DMSO-d₆) δ 13.66 (s, 1H), 13.02 (s, 1H), 9.43 (s, 1H), 8.49 (d, 1H,J=8.4 Hz), 7.72 (d, 1H, J=6.9 Hz), 7.53 (d, 1H, J=6.9 Hz), 7.44 (s, 1H),7.18-7.25 (m, 3H), 7.06 (d, 1H, J=8.1 Hz), 6.75 (d, 1H, J=2.1 Hz), 6.66(dd, 1H, J=8.1, 2.1 Hz), 250 (q, 2H, J=7.5 Hz), 1.04 (t, 3H, J=7.5 Hz).MS (ES) [m+H]/z calc'd 355, found 355; [m−H]/z calc'd 353, found 353.

Example 24(f)3-1H-Benzoimidazol-2-yl-6-(2,4-dihydroxyphenyl)-1H-indazole

62-methoxy 4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole,prepared in example 24(d), (46 mg, 0.13 mmol) was heated in pyridiniumchloride (0.5 g) at 180° C. for 2 h. The reaction was allowed to cool,and was quenched with sat. NaHCO₃ (15 mL) and extracted with EtOAc (2×20mL). Organics were dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (60% THF/hexanes) gave 26 mg(59%) of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H,J=8.4 Hz), 7.71-7.74(m, 2H), 7.50(d, 1H, J=6.9 Hz), 7.43 (dd, 1H, J=8.4,1.2 Hz), 7.16-7.23 (m, 3H), 6.45 (d, 1H, J=2.1 Hz), 6.35 (dd, 1H, J=8.4,2.1 Hz). MS (ES) [m+H]/z calc'd 343, found 343; [m−H]/z calc'd 341,found 341.

Example 24(g)3-1H-Benzoimidazol-2-yl-6-(2-phenoxy-4-hydroxyphenyl)-1H-indazole

Example 24(g) was prepared in a similar manner to that described forExample 24(c), except that 3-phenoxy-phenol was used instead of2-chloro-5-methyl-phenol in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ 13.54(s, 1H), 12.95 (s, 1H), 9.78 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.67-7.72(m, 2H), 7.49 (dd, 1H, J=6.3, 2.1 Hz), 7.43 (d, 2H, J=8.4 Hz), 7.33 (t,2H, J=7.5 Hz), 7.17-7.22 (m, 2H), 6.96-7.07 (m, 3H), 6.72 (dd, 1H,J=8.4, 2.1 Hz), 6.40 (d, 1H, J=2.1 Hz). MS (ES) [m+H]/z calc'd 419,found 419; [m−H]/z calc'd 417, found 417.

Example 24(h)3-1H-Benzoimidazol-2-yl-6-(2-(2-methoxyethyl)-4-hydroxyphenyl)-1H-indazole

Example 24(h) was prepared in a similar manner to that described forExample 24(a), except that{2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane,prepared as described below, was used instead of[24-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 13.01 (s, 1H),9.44 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.73 (br s, 1H), 7.51 (br s, 1H),7.46 (s, 1H), 7.21 (app d, 3H, J=8.1 Hz), 7.09 (d, 1H, J=8.1 Hz), 6.78(d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=8.1, 2.4 Hz), 3.40 (t, 2H, J=7.2 Hz),3.12 (s, 3H), 2.75 (t, 2H, J=7.2 Hz). MS (ES) [m+H]/z calc'd 385, found385; [m−H]/z calc'd 383, found 383.

The starting material was prepared as follows:

4-Bromo-3-(2-hydroxy-ethyl)-phenol was prepared in 88% yield by thesubstitution of 3-(2-hydroxy-ethyl)-phenol in the procedure described inExample 24(c), step (i). ¹H NMR (300 MHz, CDCl₃) δ 9.56 (s, 1H), 7.29(d, 1H, J=8.7 Hz), 6.74(d, 1H, J=3.0 Hz), 6.55 (dd, 1H, J=8.7, 3.0 Hz),4.71 (t, 1H, J=5.4 Hz), 3.52-3.59 (m, 2H), 2.73 (t, 2H, J=7.2 Hz).

Preparation of 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]was prepared in 65% yield by the substitution of4-bromo-3-(2-hydroxy-ethyl)-phenol in the procedure described in Example24(a), step (vi). ¹H NMR (300 MHz, CDCl₃) δ 7.43 (d, 1H, J=8.7 Hz), 6.97(d, 1H, J=3.0 Hz), 6.82 (dd, 1H, J=8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q,2H, J=6.6 Hz), 3.74 (t, 2H, J=8.4 Hz), 2.99 (t, 2H, J=6.6 Hz), 1.42 (t,1H, J=6.6 Hz), 0.94 (t, 2H, 1=8.4 Hz), −0.01 (s, 9H).

{(2-[Bromo-3-(2-methoxy-ethyl)phenoxymethoxy]-ethyl}-trimethyl-silane:2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g,6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and thesolution stirred for 16 h. The reaction was diluted with water (50 mL)and extracted with ether (2×40 mL). Organics were washed with brine (40mL), dried (Na₂SO₄) and concentrated in vacuo. Purification by silicagel chromatography (10% ether/hexanes) gave 1.28 g of(2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl)-trimethyl-silaneas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, 1H, J=8.7 Hz), 6.96(d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t,2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).

Example 24(i)3-1H-Benzoimidazol-2-yl-(2-(2-hydroxyethyl)-4-hydroxyphenyl)-1H-indazole

3-1H-Benzoimidazol-2-yl-6-(2-(2-methoxyethyl)-4-hydroxyphenyl)-1H-indazole,from Example 24(i), (99 mg, 0.26 mmol) was dissolved in EtOAc (20 mL)and cooled to −78° C. under argon. Boron tribromide was added dropwise,and the reaction was allowed to stir while warming to r.t over 3 h. Thesolution was diluted with EtOAc (60 mL) and washed with sat NaHCO₃ andbrine (20 mL each). Organics were dried (Na₂SO₄) and concentrated invacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%)of the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.71(br s, 1H), 7.51 (br s, 1H), 7.46 (s, 1H), 7.21 (app d, 3H, J=8.1 Hz),7.08 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.69 (dd, 1H. J=8.1, 2.1Hz), 4.57 (br s, 1H), 3.46 (t, 2H, J=7.2 Hz), 2.68 (t, 2H, J=7.2 Hz). MS(ES) [m+H]/z calc'd 371, found 371; [m−H]/z calc'd 369, found 369.

Example 24(j)3-1H-Benzoimidazol-2-yl-6-(2,6-dimethyl-4-hydroxyphenyl)-1H-indazole

Example 24(j) was prepared in a similar manner to that described forExample 24(a), except that 4-bromo-3,5-dimethyl-phenol was used insteadof 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300 MHz,DMSO-d₆) δ 13.57 (s, 1H), 12.99 (s, 1H), 9.22 (s, 1H), 8.52 (d, 1H,J=8.4 Hz), 7.72 (d, 1H, J=6.6 Hz), 7.51 (d, 1H, J=6.6 Hz), 7.31 (s, 1H),7.16-7.25 (m. 2H), 7.02 (d, 1H, J=8.4 Hz), 6.55 (s, 2H), 1.93 (s, 6H).MS (ES) [m+H]/z calc'd 355, found 355; [m−H]/z calc'd 353, found 353.

Example 24(k)3-1H-Benzoimidazol-2-yl-6-(2-methylsulfanyl-4-hydroxyphenyl)-1H-indazole

Example 24(k) was prepared in a similar manner to that described forExample 24(c), except that 3-methylsulfanyl-phenol, prepared asdescribed below, was used instead of 2-chloro-5-methyl-phenol in step(i). ¹H NMR (300 MHz, DMSO-d₆) δ 13.59 (s, 1H), 12.98 (s, 1H), 9.64 (s,1H), 8.48 (d, 1H, J=8.4 Hz), 7.71 (br s, 1H), 7.52 (app s, 2H),7.20-7.27 (m, 3H), 7.12 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=2.1 Hz), 6.65(dd, 1H, J=8.4, 2.1 Hz), 2.34 (s, 3H). MS (ES) [m+H]/z calc'd 373, found373; [m−H]/z calc'd 371, found 371.

The starting material was prepared as follows:

Preparation of 3-methylsulfanyl-phenol. 3-Hydroxythiophenol (5.0 g, 39.7mmol) and potassium carbonate (6.03 g, 43.6 mmol) were stirred inacetone (80 mL) at 0° C. Iodomethane (2.5 mL, 40 mmol) was addeddropwise, and the reaction stirred for 45 min. The solution was dilutedwith H₂O (150 mL) and extracted with EtOAc (2×100 mL). Organics werewashed with brine (100 mL), dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (25% EtOAc/hexanes) 5.08 g(91%) of 3-methylsulfanyl-phenol as a clear oil. ¹H NMR (300 MHz, CDCl₃)δ 7.15 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.74 (t, 1H, J=1.8Hz), 6.60 (dd, 1H, J=8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).

Example 24(l)3-1H-Benzoimidazol-2-yl-6-(2-(ethoxymethyl)-5-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 24(l) was prepared in a similar manner to that described forExample 24(a), except that[2-(4-bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy)-ethyl]-trimethyl-silane,prepared as described below, was used instead of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.63 (s, 1H), 12.99 (s, 1H),9.15 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.73 (dd, 1H, J=6.6, 2.1 Hz), 7.59(s, 1H), 7.51 (dd, 1H, J=6.6, 2.1 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.19-7.24(m, 2H), 6.94 (s, 1H), 6.91 (s, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 3.39(q, 2H, J=6.9 Hz), 1.13 (t, 3H, J=6.9 Hz). MS (ES) [m+H]/z calc'd 415,found 415.

The starting material was prepared as follows:

2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde wasprepared in 79% yield by the substitution of4-bromo-3-formyl-2-methoxy-phenol (Hazlet et. al., J. Org. Chem., 27,3253-55 (1962)) in the procedure described in Example 24(a), step(vi).¹H NMR (300 MHz, CDCl₃)δ 10.16(s, 1H), 7.68 (s, 1H), 7.07 (s, 1H), 5.28(s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, J=8.4 Hz), 0.94 (t, 2H, J=8.4 Hz),−0.03 (s, 9H).

Preparation of[2-(4-Bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy)-ethyl]-trimethyl-silane:Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 minto a solution of2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (1.3g, 3.6 mmol) in MeOH (20 mL) at 0° C. After 30 min, the reaction wasdiluted with H₂O (40 mL) and extracted with EtOAc (2×30 mL). Organicswere washed with brine (30 mL), dried (Na₂SO₄) and concentrated in vacuoto give 1.31 g of[2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-methanolas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.29 (s, 1H), 7.05 (s, 1H),5.27 (s, 2H), 4.66 (d, 2H, J=6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, J=8.4Hz), 1.92 (t, 1H, J=6.6 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).

The crude benzyl alcohol was stirred with a solution of potassiumhydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). Iodoethane (580 mL, 7.2mmol) was added, and the reaction stirred for 16 h before it was dilutedwith H₂O (30 mL) and extracted with ether (2×30 mL). Organics werewashed with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.30g (92%) of the title compound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H),3.79 (t, 2H, J=8.4 Hz), 3.58 (q, 2H, J=6.9 Hz), 1.26 (t, 3H, J=6.9 Hz),0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).

Example 24(m) 3-1H-Benzoimidaz1-2-yl-6-(2-(hydroxymethyl)-4-ethoxy-5-methoxy-phenyl)-1H-indazole

Example 24(m) was prepared in a similar manner to that described forExample 24(a), except that [2-(2-bromo-5-ethoxy4-methoxy-benzyloxymethoxy)-ethyl]-trimethyl-silane, prepared asdescribed below, was used instead of[2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy) ethyl]-trimethylsilane instep (vii). ¹H NMR (300 MHz, DMSO-d₆) δ 13.64 (s, 1H), 13.00 (s, 1H),8.50 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 7.52 (dd,1H, J=6.0, 1.8 Hz), 7.32(dd, 1H, J=8.4, 1.2 Hz), 7.19-7.24 (m, 2H), 7.15(s, 1H), 6.91 (s, 1H), 5.11 (t, 1H, J=5.1 Hz), 4.37 (d, 2H, J=5.1 Hz),4.08 (q, 2H, J=6.9 Hz), 3.80 (s, 3H), 1.37 (t, 3H, J=6.9 Hz). MS (ES)[m+H]/z calc'd 415, found 415.

The starting material was prepared as follows:

Preparation of 4-bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)phenol:[2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxmethoxy)-phenyl]-methanol,upon sitting for periods of over a week, underwent SEM-migration fromthe phenolic to the benzylic alcohol to yield the title compound. ¹H NMR(300 MHz, CDCl₃) δ 7.04 (s, 1H), 7.01 (s, 1H), 5.54 (s, 1H), 4.77 (s,2H), 4.57 (s, 2H), 3.88 (s, 3H), 3.68 (t, 2H, J=8.4 Hz), 0.97 (t, 2H,J=8.4 Hz), 0.02 (s, 9H).

Preparation of[2-(2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy)-ethyl]-trimethyl-silane:4-Bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)-phenol (1.28 g,3.53 mmol) was stirred with a solution of potassium hydroxide (790 mg,14.1 mmol) in DMSO (8 mL). Iodoethane (565 mL, 7.1 mmol) was added, andthe reaction stirred for 16 h before it was diluted with H₂O (30 mL) andextracted with ether (2×30 mL). Organics were washed with brine (20 mL),dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gelchromatography (15% EtOAc/hexanes) gave 1.26 g (91%) of the tidecompound as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.02 (s, 1H), 6.98(s, 1H), 4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H, J=6.6 Hz), 3.86 (s,3H), 3.69 (t, 2H, J=8.4 Hz), 1.46 (t, 3H, J=6.6 Hz), 0.97 (t, 2H, J=8.4Hz), 0.04 (s, 9H).

Example 24(n)3-1H-Benzoimidazol-2-yl-6-(2-(hydroxymethyl)-5-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 24(n) was prepared in a similar manner to that described forExample 24(a), except that6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole,prepared as described below, was used instead of6-[5-methoxy-2-methyl(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)1H-benzoimidazol-2-yl]-1H-indazole. ¹H NMR (300 Mz, DMSO-d₆) δ 13.59 (s,1H), 12.95 (s, 1H), 9.05 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.72 (dd, 1H,J=6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 (dd, 1H, J=6.3, 2.1 Hz), 7.31 (d, 1H,J=8.4 Hz), 7.20-7.24 (m, 2H), 7.02 (s, 1H), 6.87 (s, 1H), 5.02 (t, 1H.J=5.4 Hz), 4.32 (d, 2H, J=5.4 Hz), 3.80 (s, 3H). MS (ES) [m+H]/z calc'd387, found 387; [m−H]/z calc'd 385, found 385.

The starting material was prepared as follows:

Preparation of4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde:2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde(3.36 g, 9.3 mmol) and hexamethylditin (5.0 g, 15.3 mmol) were stirredin dry toluene (60 mL) in a flask purged with argon.Tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.45 mmol) was added,and the reaction stirred at 100° C. for 23 h. The reaction was cooledand concentrated in vacuo. Purification by silica gel chromatography (5%EtOAc/hexanes) gave 2.77 g (67%) of4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehydeas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 9.81 (dd, 1H, J=3.0, 0.9 Hz),7.66 (t, 1H, J=6.6 Hz), 7.21 (t, 1H, J=9.0 Hz), 5.35 (s, 2H), 3.99 (s,3H), 3.82 (t, 2H, J=8.4 Hz), 0.25 (t, 9H, J=26.7 Hz), 0.98 (t, 2H, J=8.4Hz), −0.01 (s, 9H).

Preparation of[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol:4-Methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde(2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0° C. Sodiumborohydride (400 mg, 10.6 mmol) was added, and the reaction stirred for1 h. The solution was diluted with H₂O (60 mL), and extracted with EtOAc(2×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), andconcentrated in vacuo to give 2.16 g (91%) of[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanolas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t, 1H, J=6.9 Hz), 7.03(t, 1H, J=9.3 Hz), 5.27 (s, 2H), 4.584.63 (m, 2H), 3.89 (s, 3H), 3.80(t, 2H, J=8.4 Hz), 1.53 (t, 1H, J=6.0 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.31(t, 9H, J=27.3 Hz), 0.01 (s, 9H).

Preparation of6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole:6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole[Example 24(a), step (v)] (300 mg, 0.48 mmol) and[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol(282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C.for 16 h. The reaction was allowed to cool and was diluted with EtOAc.Organics were washed with sat NaHCO₃ and brine, dried (Na₂SO₄), andconcentrated in vacuo. Purification by silica gel chromatography (20%EtOAc/hexanes) gave 224 mg (60%) of6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazolas a faint yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, 1H, J=8.4 Hz),7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H), 6.91 (s, 1H),6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78-3.92 (m,5H), 3.59-3.70 (m, 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H); −0.04 (s, 9H),−0.13 (s, 9 Hz).

Example 24(o) 3-1H-Benzoimidazol-2-yl-6-(3-hydroxyphenyl)-1H-indazole

Example 24(o) was prepared in a similar manner to that described forExample 24(f), except that6-(3-methoxy-phenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in asimilar manner to that described for example 24(a) except that3-methoxy-phenylboronic acid was used instead of5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylboronicacid in step (viii), was used instead of6-(2-methoxy-4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole. ¹HNMR (300 MHz, DMSO-d₆) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H),8.55 (d, 1H, J=8.4 Hz), 7.71-7.75 (m, 2H), 7.49-757 (m, 2H), 7.30 (t,1H, J=7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES)[m+H]/z calc'd 327, found 327; [m−H]/z calc'd 325, found 325.

Example 24(p)3-1H-Benzoimidazol-2-yl-6-(2-methoxy-3-hydroxyphenyl)-1H-indazole

Example 24(p) was prepared in a similar manner to that described forExample 24(a), except that 3-bromo-2-methoxy-phenol, prepared asdescribed by Aristoff et. al., Tet. Lett., 25, 3955-58 (1984) was usedinstead of 4-bromo-2-methoxy-5-methyl-phenol in step (vi). ¹H NMR (300MHz, DMSO-d₆) δ 13.60 (s, 1H), 12.97 (s, 1H), 9.37 (s, 1H), 8.52 (d, 1H,J=8.4 Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H, J=7.8, 1.8 Hz), 7.43 (dd,1H, J=8.4, 1.2 Hz), 7.19-7.24 (m, 2H), 7.02 (t, 1H, J=7.8 Hz), 6.85-6.93(m, 2H), 3.50 (s, 3H). MS (ES) [m+H]/z calc'd 357, found 355, [m−H]/zcalc'd 357, found 355.

Example 25(a)3-(3H-Imidazo[4,5-c]pyridin-2-yl)-6-hydroxy-2-methoxyphenyl)-1H-indazole

A solution of of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazole(68 mg, 0.11 mmol) in TBAF (1 M in THF, 1.2 mL, 1.2 mmol) withethylenediamine (150 mL, 2.2 mmol) was stirred at 68° C. for 48 h. Thesolution was concentrated in vacuo and purified by silica gelchromatography (2:1 EtOH/EtOAc). Precipitation from acetonitrile gave 21mg (53%) of3-(3H-imidazo[4,5]pyridin-2-yl)(4-hydroxy-2-methoxyphenyl)-1H-indazoleas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.70 (s, 1H), 13.49 (brs, 1H), 9.62 (s, 1H), 9.01 (br s, 1H), 8.43 (d, 1H, J=8.7 Hz), 8.34 (d,1H, J=5.7 Hz), 7.64 (s, 1H), 7.57 (br s, 1H), 7.39 (dd, 1H, J=8.7, 1.5Hz), 7.21 (d, 1H, J=8.1 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.49 (dd, 1H,J=8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [m+H]/z calc'd 358, found 358;[m−H]/z calc'd 356, found 356.The intermediates were prepared as follows:

3-(1,1-Dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole.A solution of6-iodo-3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazole(Example 14, step (i)] (1.28 g, 2.69 mmol) in CH₂Cl₂ (40 mL)/MeOH (40mL) was stirred at −78° C. The reaction was treated with ozone until ablue color persisted, and then was purged with argon. Methyl sulfide (4mL) was added, and the reaction stirred 4 h while warning to r.tConcentration in vacuo gave a crude mixture of acetal and aldehyde,which was converted completely to the acetal by stirring in trimethylorthoformate (10 mL) with Amberlyst 15(wet) acidic ion-exchange resin(0.8 g) for 1 h. The resin was removed by filtration, and the solutionwas concentrated in vacuo. Purification by silica gel chromatographygave 1.11 g (92%) of3-(1,1-dimethoxy-methyl-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (s, 1H), 7.68 (d, 1H,J=8.4 Hz), 7.48 (dd, 1H, J=8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H),3.53 (t, 2H, J=8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J=8.4 Hz), −0.06 (s,9H).

3-(1,1-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole.3-(1,1-Dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(1.06 g, 2.37 mmol),2-methoxy-4-(trimethylsilanyl-ethoxymethoxy)phenylboronic acid (0.99 g,3.32 mmol), and sodium carbonate (352 mg, 1.4 mmol) were stirred in amixture of benzene (15 mL), MeOH (3 mL), and water (1 mL) in a flaskpurged with argon. Tetrakis(triphenylphosphine)palladium(0) (220 mg,0.19 mmol) was added, and the reaction stirred at reflux for 16 h. Thereaction was allowed to cool and was diluted with ether (70 mL).Organics were washed with H₂O and brine (30 mL each), dried (Na₂SO₄),and concentrated in vacuo. Purification by silica gel chromatography(15% EtOAc/hexanes) gave 1.12 g (82%) of3-(1,1-dimethoxy-methyl)-6-[2-methoxy4-(2-trimethylsilanyl-ethoxymethoxy)phenyl]1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a faintly yellow oil.¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, 1H, J=8.4 Hz), 7.64 (s, 1H), 7.37(dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, H, J=8.4 Hz), 6.71-6.77 (m, 2H), 5.82(s, 1H), 5.75 (s, 2H), 5.28 (s, 2H), 3.77-3.83 (m, 5H), 3.57 (t, 2H,J=8.4 Hz), 3.46 (s, 6H), 1.00 (t, 2H, J=8.4 Hz), 0.88 (t, 2H, J=8.4 Hz),0.03 (s, 9H), −0.05 (s, 9H).

6-[2-Methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde.3-(1,1-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(1.1 g, 1.92 mmol) was stirred in 1% TFA/CH₂Cl₂ (20 mL) for 1 h at rtConcentration in vacuo yielded 1.01 g (100%) of6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydeas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 10.27 (s, 1H), 8.28 (d, 1H,J=8.4 Hz), 7.73 (s, 1H), 7.55 (dd, 1H, J=8.4, 1.2 Hz), 7.29 (d, 1H,J=8.4 Hz), 6.72-6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.78-3.84 (m,5H), 3.61 (t, 2H, J=8.1 Hz), 0.89-1.03 (m, 4H), 0.03 (s, 9H), −0.05 (s,9H).

[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazole.6-[2-Methoxy4-(2-trimethyl-silanyl-ethoxymethoxy)phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(320 mg, 0.61 mmol), 3,4-diamino-pyridine (68 mg, 0.62 mmol), and sulfur(23 mg, 0.73 mmol) were combined in dry DMF (2 mL) and stirred at 90° C.for 16 h under argon. The reaction was allowed to cool and was dilutedwith EtOAc (20 mL). Organics were washed with sat. NaHCO₃ and brine (15mL each), dried (Na₂SO₄), and concentrated in vacuo. Purification bysilica gel chromatography (75% to 100% EtOAc/hexanes) gave 78 mg (21%)of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazoleas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 10.69 (br s, 1H), 9.21 (s,1H), 8.63 (dd, 1H J=8.4, 0.3 Hz), 8.50 (d, 1H, J=5.4 Hz), 7.73 (s, 1H),7.47 (br s, 1H), 7.57 (dd, 1H, J=8.7, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz),6.746.80 (m, 2H), 5.80 (s, 2H), 5.29 (s, 2H), 3.78-3.85 (m, 5H), 3.63(t, 2H, J=8.1 Hz), 0.89-1.04 (m, 4H), 0.04 (s, 9H), 0.06 (s, 9H).

Example 25(b)3-[6-(2-morpholin-4-yl-ethylcarbamoyl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

Example 25(b) was prepared in a similar manner to that described forExample 25(a), except that3,4-diamino-N-(2-morpholin-1-yl-ethyl)-benzamide, prepared as describedbelow, was used instead of 3,4-diaminopyridine in step (iv). ¹H NMR (300MHz, DMSO-d₆) δ 13.61 (s, 05H), 13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18(s, 0.5H), 9.59 (s, if H), 8.35-8.46 (m, 2H), 8.27 (s, 0.5H), 8.02 (s,0.5H), 7.71-7.79 (m, 1.5H), 7.63 (s, 1H), 7.53 (d, 0.5H, J=8.7 Hz), 7.38(d, 1H, J=8.7 Hz), 7.21 (d, 1H, J=8.7 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.49(dd, 1H, J=8.4, 2.1 Hz), 3.75 (s, 3H), 3.58 (t, 4H, J=4.5 Hz), 3.42 (q,2H, J=6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [m+H]/z calc'd 513, found 513;[m−H]/z calc'd 511, found 511.3,4-Diamino-N-(2-morpholin-4-yl-ethyl)-benzamide was prepared asfollows:

3,4-Diamino-N-(2-morpholin-4-yl-ethyl)-benzamide. 3,4-Diaminobenzoicacid (5 g, 32.9 mmol), 4-(2-aminoethyl)morpholine (5.2 mL, 39.4 mmol),triethylamine (9.2 mL, 66 mmol), and DMAP (0.40 g, 3.3 mmol) werecombined in dry DMF (80 mL) at 0° C. EDC (9.45 g, 49.3 mmol) was added,and the reaction stirred for 24 h at r.t. Concentration in vacuo andpurification by silica gel chromatography (10% MeOH/CH₂Cl₂ with 0.2%NH₄OH) gave 2.6 g (31%) of3,4-diamino-N-(2-morpholin-4-yl-ethyl)-benzamide as a light brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (t, 1H, J=5.4 Hz), 7.02 (d, 1H, J=1.8Hz), 6.92 (dd, 1H, J=8.1, 1.8 Hz), 6.46 (d, 1H, J=8.1 Hz), 4.89 (br s,2H), 4.51 (br s, 2H), 3.55 (t, 4H, J=4.8 Hz), 3.29 (q, 2H, J=7.2 Hz),2.36-2.43 (m, 6H).

Example 25(c)3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

Example 25(c) was prepared in a similar manner to that described forExample 25(a), except 4-(4-methyl-piperazin-1-yl)benzene-1,2-diamine(Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)) was usedinstead of 3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ13.51 (s, 0.33H), 13.38 (s, 0.67H), 12.66 (s, 0.33H), 12.59 (s, 0.67H),9.58 (s, 1H), 8.42 (d, 0.33H, J=8.4 Hz), 8.41 (d, 0.67H, J=8.4 Hz), 7.59(s, 1H), 7.55 (d, 0.67H, J=8.7 Hz), 7.31-7.37 (m, 1.33H), 7.20 (app d,1.33H, J=8.4 Hz), 6.92-7.01 (m, 1.67H), 6.55 (d, 1H, J=1.5 Hz), 6.48(dd, 1H, J=8.4, 2.1 Hz), 3.74 (s, 3H), 3.12 (br s, 4H), 2.50 (br s, 4H),2.22 (s, 3H). MS (ES) [m+H]/z calc'd 455, found 455; [m−H]/z calc'd 453,found 453.

Example 25(d)3-[4-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

Example 25(d) was prepared in a similar manner to that described forExample 25(a), except 3-(4-methyl-piperazin-1-yl)-benzene-112-diamine(Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)), analogous tothe 4-isomer preparation) was used instead of 3,4-diaminopyridine instep (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (br s, 1H), 12.79 (br s,1H), 9.60 (br s, 1H), 8.37 (d, 1H, J=8.4 Hz), 7.60 (s, 1H), 7.36 (dd,1H, J=8.4, 1.2 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.03-7.07 (m, 2H), 6.46-6.56(m, 3H), 3.75 (s, 3H), 3.62 (br s, 4H), 2.62 (br s, 4H), 2.28 (s, 3H).MS (ES) [m+H]/z calc'd 455, found 455; [m−H]/z calc'd 453, found 453.

Example 25(e) 3-imidazol-2-yl-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

Example 25(e) was prepared in a similar manner to that described forExample 25(a), except6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-imidazol-2-yl-1H-indazolewas used instead of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazole.¹H NMR (300 MHz, DMSO-d₆) δ 13.10 (s, 1H), 12.59 (s, 1H), 9.56 (s, 1H),8.27 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.25 (dd, 1H, J=8.4, 1.2 Hz),7.13-7.20 (m, 3H), 6.54 (d, 1H, J=2.1 Hz), 6.47 (dd, 1H, J=8.4, 2.1 Hz),3.73 (s, 3H). MS (ES) [m+H]/z calc'd 307, found 307.The starting material was prepared as follows:

Glyoxal (40 wt % in H₂O, 0.4 mL, 3.5 mmol) was added dropwise to asolution of 420 mg (0.8 mmol) 6-[2-methoxy(2-trimethylsilanyl-ethoxymethoxy)phenyl]-1-2-trimethylsilanyl-ethoxymethyl)1H-indazole-3-carbaldehyde,from Example 25(a) step (iii), and 28% aqueous ammonia (0.6 mL) in THF(8 mL)/MeOH (8 mL), and the solution was stirred at r.t. for 16 h. Thereaction was concentrated in vacuo and dissolved in CHCl₃ (50 mL).Organics were washed with H₂O and brine (25 mL each), dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel chromatography (40%EtOAc/hexanes) gave 120 mg (27%) of6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-3-imidazol-2-yl-1H-indazoleas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 10.03 (s, 1H), 8.48 (d, 1H,J=8.4 Hz), 7.65 (s, 1H), 7.46 (dd, 1H, J=8.4, 1.5 Hz), 7.29-7.48 (m,2H), 7.13 (d, 1H, J=1.5 Hz), 6.73-6.78 (m, 2H), 5.73 (s, 2H), 5.28 (s,2H), 3.78-3.86 (m, 5H), 3.60 (t, 2H, J=8.4 Hz), 0.88-1.03 (m, 4H), 0.03(s, 9H), −0.05 (s, 9H).

Example 25(f)3-[4-(2-hydroxyethylsulfanyl)-1H-benzoimidazol-2-yl]-6-(2-methoxy-4-hydroxyphenyl)-1H-indazole

Example 25(f) was prepared in a similar manner to that described forExample 25(a), except that 2-(2,3-diamino-phenylsulfanyl)-ethanol) wasused instead of 3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz,DMSO-d₆) δ 13.51 (s, 1H), 13.02 (s, 1H), 9.59 (s, 1H), 8.45 (d, 1H,J=8.4 Hz), 7.61 (s, 1H), 7.32-7.40 (m, 2H), 7.11-7.23 (m, 3H), 6.55 (d,1H, J=2.4 Hz), 6.48 (dd, 1H, J=8.1, 2.4 Hz), 4.96 (br s, 1H), 3.75 (s,3H), 3.65 (br s, 2H), 3.33 (t, 2H, J=6.9 Hz). MS (ES) [m+Na]/z calc'd455, found 455, [m−H]/z calc'd 431, found 431.

The starting material was prepared as follows:

2-(3-Amino-2-nitro-phenylsulfanyl)ethanol. 3-Chloro-2-nitro-aniline(1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml, 8.6 mmol), and potassiumcarbonate (0.99 g, 7.1 mmol) were combined in dry DMF (15 ml) andstirred at 130° C. for 4 h. The solution was allowed to cool and wasconcentrated in vacuo. Purification by silica gel chromatography (70%EtOAc/hexanes) gave 1.29 g (93%) of 23-amino-2-nitrophenylsulfanyl)-ethanol as a bright red solid. ¹H NMR (300 MHz, DMSO-d₆)δ 7.20 (t, 1H, J=8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J=8.4, 0.9 Hz),6.63 (dd, 1H, J=7.8, 1.2 Hz), 4.92 (t, 1H, J=6.0 Hz), 3.58 (q, 2H, J=6.0Hz), 2.98 (t, 2H, J=6.0 Hz).2-(2,3-Diamino-phenysulfanyl)-ethanol. 2-(3-Amino-2-nitrophenylsulfanyl)ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi ofH₂ with 10% Pd-C (180 mg) in EtOAc (25 mL) for 6 h. After filteringthrough Celite, solvent was removed in vacuo. Purification by silica gelchromatography (EtOAc) gave 762 mg (87%) of22,3-diamino-phenylsulfanyl)ethanol as a faintly yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 6.98 (dd, 1H, J=7.5, 1.5 Hz), 6.606.72 (m, 2H), 3.65(t, 2H, J=5.7 Hz), 355 (br s, 5H), 2.91 (t, 2H, J=5.7 Hz). Example25(g); 3-(5-methylcarbamoyl-1H-benzoimidazol-2-yl)-6-(2-methoxy-4hydroxyphenyl)-1H-indazole

Example 25(g) was prepared in a similar manner to that described forExample 25(a), except 3,4-diamino-N-methyl-benzamide (Kumar, et. al. J.Med. Chem, 27, 1083-89 (1984)) was used instead of 3,4-diaminopyridinein step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.59 (s, 0.5H), 13.55 (s,0.5H), 13.21 (s, 0.5H), 13.14 (s, 0.5H), 9.60 (s, 1H), 8.38-9.46 (m,2H), 8.26 (s, 0.5H), 8.03 (s, 0.5H), 7.71-7.79 (m, 1.5H), 7.63 (s, 1H),7.52 (d, 0.5H, J=8.4 Hz), 7.35-7.40 (m, 1H), 7.21 (d, 1H, J=2.1 Hz),6.55 (d, 1H, J=2.4 Hz), 6.49 (dd, 1H, J=8.4, 2.4 Hz), 3.75 (s, 3H), 2.82(d, 1.5H, J=1.5 Hz). 2.81 (d, 1.5H, J=1.5 Hz). MS (ES) [m+H]/z calc'd414, found 414, [m−H]/z calc'd 412, found 412.

Example 25(h)3-(5-Dimethylamino-1H-benzoimidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 25 (h) was prepared in a similar manner to that described forExample 25(a), except 3,4-diamino-N,N-dimethyl-aniline (Cazaux, et. al.,Can. J. Chem., 71, 1236-46 (1993)) was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (s,1H), 12.51 (br s, 1H), 9.58 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 7.59 (s,1H), 7.49 (br s, 1H), 7.33 (dd, 1H, J=8.4, 1.2 Hz), 7.20 (d, 1H, J=8.1Hz), 6.87 (br d, 2H, J=8.1 Hz), 6.55 (d, 1H, J=2.1 Hz), 6.48 (dd, 1H,J=8.1, 2.1 Hz), 3.73 (s, 3H), 2.92 (s, 6H). MS (ES) [m+H]/z calc'd 400,found 400, [m−H]/z calc'd 398, found 398.

Example 25(i)3-(5-Aminosulfonyl-1H-benzoimidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 25(i) was prepared in a similar manner to that described forExample 25(a), except 3,4-diamino-benzenesulfonamide was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆) δ 13.67 (s,0.5H), 13.64 (s, 0.5H), 13.39 (s, 0.5H), 13.35 (s, 0.5H), 9.60 (s, 1H),8.43 (d, 1H, J=8.1 Hz), 8.18 (d, 0.5H, J=1.5 Hz), 7.99 (d, 0.5H, J=1.5Hz), 7.86 (d, 0.5H, J=8.4 Hz), 7.62-7.72 (m, 2.5H), 7.29 (d, 1H, J=8.4Hz), 7.20-7.28 (m, 3H), 6.55 (d, 1H. J=2.1 Hz), 6.49 (dd, 1H, J=8.4, 2.1Hz), 3.75 (s, 3H). MS (ES) [m+H]/z calc'd 436, found 436, [m−H]/z calc'd434, found 434.

Example 25(i)3-(4-methylcarbamoyl-1H-benzolmidazol-2-yl)-6-(2-methoxy-4-hydroxy-phenyl)-1H-indazole

Example 25(i) was prepared in a similar manner to that described forExample 25(a), 2,3-diamino-N-methyl-benzamide was used instead of3,4-diaminopyridine in step (iv). ¹H NMR (300 MHz, DMSO-d₆)δ 13.71 (s,1H), 13.46(s, 1H), 9.85 (br d, 1H, J=4.8 Hz), 9.61 (s, 1H), 8.38 (d, 1H,J=8.4 Hz), 7.89 (dd, 1H, J=7.5, 1.2 Hz), 7.66-7.72 (m, 2H), 7.47 (dd,1H, J=8.4, 1.2 Hz), 7.36(t, 1H, J=7.8 Hz), 7.23 (d, 1H, J=8.1 Hz), 6.56(d, 1H, J=2.4 Hz), 6.50 (dd, 1H, J=8.4, 2.4 Hz), 3.76 (s, 3H), 3.10 (d,3H, J=1.8 Hz). MS (ES) [m+H]l/z calc'd 414, found 414, [m−H]/z calc'd412, found 412.2,3-Diamino-N-methyl-benzamide was prepared as follows:

2-Amino-N-methyl-3-nitro-benzamide. 2-Amino-3-nitro-benzoic acid (1.8 g,9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol), werestirred in dry CH₂CO₂ (30 ml)/DMF (5 mL) at 0° C. EDC (2.83 g, 14.8mmol) and DIEA (4.92 mL 27.7 mmol) were added, and the solution stirred3 h while warming to r.t. The reaction was concentrated in vacuo andpurified by silica gel chromatography (8% MeOH/CHCl₃) to give 1.42 g(74%) of 2-amino-N-methyl-3-nitro-benzamide as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 8.58 (br s, 1H), 8.23 (br s, 2H), 8.15 (dd, 1H,J=8.1, 1.8 Hz), 7.82 (dd, 1H, J=8.1, 1.8 Hz), 6.68 (t, 1H, J=8.1 Hz),2.76 (d, 3H, J=4.5 Hz).2,3-Diamino-N-methyl-benzamide. 2-Amino-N-methyl-3-nitro-benzamide (1.4g, 7.2 mmol) was reduced by hydrogenation using 50 psi of H₂ with 10%Pd-C (250 mg) in EtOAc (25 mL) for 5 h. After filtering through Celite,solvent was removed in vacuo. Purification by silica gel chromatography(10% MeOH/CHCl₃) gave 1.08 mg (91%) of 2,3-diamino-N-methyl-benzamide asa faintly yellow solid. ¹H NMR (300 MHz, CDCl ₃) δ 6.87 (dd, 1H, J=7.8,1.5 Hz), 6.76 (dd, 1H, J=7.8, 1.5 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.14 (brs, 1H), 4.28 (br s, 4H), 2.95 (d, 3H, J=5.1 Hz).

Example 266-(4-Hydroxy-3-methoxyphenyl)-3-[E-2-(4-glycylamino-phenyl)-ethenyl]-1H-indazole

Example 26 was prepared from the starting material described below in asimilar manner to that described for Example 1(a): ¹H N (300 MHz, CDCl₃)δ 8.29 (d, 1H), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 (s, H), 7.27 (d, 1H),7.01 (d, 1H), 4.00 (s, 3H), 3.42 (s, 2H); LCMS (100% area) Rt=3.44 min,(pos) [M+H]/z Calc'd 415.1, found 415.2.The starting material was prepared as follows:

3-Iodo-6-(3-methoxy-4-methoxymethoxy-phenyl 1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole was prepared from the compound prepared inExample 1(a), step (v) in a similar manner to that described for Example10, step (ii): R_(f) sm 0.11, p 0.43 (ethyl acetate-hexane 3:7); ¹H NMR(300 MHz, CDCl₃) δ 7.71 (s, 1H), 7.55 (m, 2H), 7.33 (m, 1H), 7.20 (m,2H), 5.82 (s, 2H), 5.33 (s, 2H), 4.02 (s, 3H), 3.64 (t, 2H), 3.59 (s,3H), 0.95 (t, 2H), −0.03 (s, 9H).

3-Styryl-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared in a similar manner to that described for Example 11, step(iii): R_(f) sm 0.41, p 0.35 (ethyl acetate-hexane 2:8); ¹H NMR (300MHz, CDCl₃) δ 8.12 (d, 1H), 7.73 (s, 1H), 7.62 (m, 2H), 7.51 (m, 2h),7.46 (m, 2H), 7.38 (m, 1H), 7.30 (m, 4H), 5.85 (s, 2H), 5.38 (s, 2H),4.03 (s, 3H), 3.70 (t, 2H), 3.62 (s, 3H), 0.98 (t, 2H), −0.02 (s, 9H).

3-Carboxaldehyde-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazolewas prepared in a similar manner to that described for Example 33(a),step (i): ¹H NMR (300 MHz, CDCl₃) δ 10.33 (s, 1H), 8.34 (d, 1H), 7.82(s, 1H), 7.65 (d, 1H), 7.25 (m, 3H), 5.90 (s, 2H), 5.36 (s, 2H), 4.02(s; 3H), 3.67 (t, 2H), 3.51 (s, 3H), 0.98 (t, 2H), −0.02 (s, 9H).

3-(4-Nitrostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-[2-(trimethyl-silanylethoxymethyl]-1H-indazole was prepared in a similar manner to thatdescribed for Example 33(a), step (ii) except that4-nitrobenzyltriphenylphosphonium bromide and lithiumhexamethyldisilazide were used instead of 2-picolyltriphenylphosphoniumchloride-potassium hydride: LCMS (100% area) Rt=6.89 min, (pos) [M+H]/zCalc'd 562.4, found 562.4.

3-(4-Nitrostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole wasprepared in a similar manner to that described for Example 11: FTIR(thin film) 3335, 3178, 2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136,987 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, 2H, J=8.8 Hz), 8.02 (d, 1H,J=8.5 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.58 (m, 3H), 7.45 (dd, 1H, J=1.3,8.5 Hz), 7.20 (m, 4H), 7.26 (s, 2H), 3.95 (s, 3H), 3.53 (s, 3H); LCMS(100% area) Rt=5.13 min, (pos) (M+H]/z Calc'd 432.1, found 432.1.

3-(4-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole wasprepared in a similar manner to that described for Example 11, step(iv): R_(f) sm 0.39, p 0.26 (ethyl acetate-hexane 6:4); FTIR (thin film)3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077, 989, 912cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.11 (d, 1H), 7.63 (s, 1H), 7.50-7.15(m, 8H), 6.71 (d, 2H), 5.36 (s, 2H), 3.97 (s, 3H), 3.61 (s, 3H); LCMS(100% area) Rt=4.40 min, (pos) [M+H]/z Calc'd 402.2, found 402.2.

3-(4-aminostyryl)-4-(3-methoxy-4-methoxymethoxy-phenyl) 1H-indazole (90mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treatedwith Boc-glycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) andHATU (426 mg, 5 equiv). The mixture was allowed to stir for 30 min. Themixture was partitioned between ethyl acetate and water. The organicmaterial was concentrated, taken up in methanol (5 mL) and was treatedwith potassium carbonate (100 mg). The mixture was heated to 50° C. for3 d. The resulting mix was again partitioned between ethyl acetate andwater. The organic material was concentrated, and purified by silica(109 mg, 66%): R_(f) sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); ¹H NMR(300 MHz, CDCl₃) δ 8.18 (bs, 1H), 8.03 (d, 1H, J=8.1 Hz), 7.56 (m, 5H),7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (bs, 1H), 3.98 (s, 3H),3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).

Example 27(a) 6-phenyl-3-E-styryl-1H-indazole

6-phenyl-3-styryl-11[2-(trimethyl-silanyl-ethoxymethyl]-1H-indazole (345mg, 0.81 mmol) was treated with a solution of TBAF (16 ml of a 1 Msolution in THF, 16 mmol), and ethylene diamine (0.53 ml, 8.1 mmol), andheated at 70° C. for 2 h. The solution was then poured into brine (200ml), and extracted with ethyl acetate (3×30 ml). The organic layer wasdried over MgSO₄, and concentrated under reduced pressure. Purificationby silica gel chromatography gave 6-phenyl-3-E-styryl-1H-indazole as awhite solid (80 mg, 34%): ¹H N (300 MHz, CDCl₃) δ 8.10 (d, 1H, J=8.5Hz); HRMS (FAB) [M+H]/z Calc'd 297.1392, found 297.1393. Anal. Calc'd, C(85.10), H (5.44), N (9.45). Found: C (85.10), H (5.46), N (9.43).The starting material was prepared as follows:

A solution of 476 mg (1.0 mmol) of6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H— indazole, fromExample 14 step (i), in dioxane (3 ml, degassed by sonication andbubbling argon), Pd(PPh₃)₄ (23 mg, 0.05 mmol), phenylboronic acid (302mg, 2.5 mmol), and Na₂CO₃ (1.25 ml of a 2M aqueous solution, degassed asabove) was heated at 90° C. for 2 h. The solution was then diluted withethyl acetate (100 ml) and washed with brine (2×20 ml). The organiclayer was dried over MgSO₄, and concentrated under reduced pressure.Purification by silica gel chromatography gave of6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H— indazole asa brown oil (345 mg, 81%). ¹H NMR (300 MHz, CDCl₃) δ 8.09 (dd, 1H,J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.647.58 (m. 2H),7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m,1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).

Example 27(b) 6-(3-methoxyphenyl)-3-E-styryl-1H-indazole

Example 27(b) was prepared in a similar manner to that described forExample 27(a), except that 3-methoxyphenylboronic acid was used insteadof phenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d₄) δ 8.16 (d,1H, J=8.4 Hz), 7.70 (s, 1H), 7.67-7.61 (m, 2H), 7.60-7.43 (m, 3H),7.43-7.33 (m, 3H), 7.32-7.21 (m, 3H), 6.99-6.92 (m, 1H), 3.88 (s, 3H).HRMS (FAB) [M+Na]/z Calc'd 349.1317, found 349.1342. Analyzed with0.1H₂O Calc'd, C (80.50), H (5.59), N (855). Found: C (80.44), H (5.49),N (8.55).

Example 27(c) 6-(4-methoxyphenyl)-3-E-styryl-1H-indazole

Example 27(b) was prepared in a similar manner to that described forExample 27(a), except that 4-methoxyphenylboronic acid was used insteadof phenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (s,1H), 8.23 (d, 1H, J=8.4 Hz), 7.767.64 (m, 5H), 7.54 (s, 1H), 7.50-7.37(m, 3H), 7.33-7.25 (m, 1H), 7.07 (d, 2H, J=8.8 Hz), 3.82 (s, 3H)HRMS(FAB) [M+H]/z Calc'd 327.1497, found 327.1502. Anal. Calc'd, C (80.96),H (5.56), N (8.58). Found: C (80.71), H (5.42), N (8.47).

Example 27(d) 6-naphth-1-yl-3-E-styryl-1H-indazole

Example 27(d) was prepared in a similar manner to that described forExample 27(a), except that 1-naphthaleneboronic acid was used instead ofphenylboronic acid in step (i) ¹H NMR (300 MHz, DMSO-d₆) δ 10.11 (s,1H), 8.45 (d, 1H. J=8.41), 7.97-7.87 (m, 3H), 7.66-7.37 (m, 13H),7.35-7.28 (m, 1H). HRMS (FAB) [M+Na]/z Calc'd 369.1368, found 369.1359.Anal. Calc'd C (86.68), H (5.32), N (8.19). Found: C (86.52), H (5.32),N (8.19).

Example 27(e) 6-pyridin-3-yl-3-E-styryl-1H-indazole

Example 27(e) was prepared in a similar manner to that described forExample 27(a), except that 3-pyridineboronic acid was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d₄) δ 8.97 (s,1H), 8.63 (d, 1H, J=4.8 Hz), 8.30 (d, 1H, H=8.5 Hz), 8.27 (d, 1H, J=8.1Hz), 7.86 (s, 1H), 7.72 (d, 2H, J=7.5 Hz), 7.69-7.56 (m, 4H), 7.54-7.42(m, 2H), 7.40-7.32 (m, 1H). HRMS (FAB) [M+H]/z Calc'd 298.1344, found298.1356. Analyzed with 0.25H₂O Calc'd, C (79.58), H (5.18), N (13.92).Found: C (79.53), H (5.16), N (13.80).

Example 27(f) 6-pyridin-4-yl-3-E-styryl-1H-indazole

Example 27(f) was prepared in a similar manner to that described forExample 27(a), except that 4-pyridineboronic acid was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d₄) δ 8.69 (bs,2H), 8.30 (d, 1H, J=8.5 Hz), 7.96 (s, 1H), 7.87 (d, 2H, H=5.6 Hz),7.75-7.68 (m, 3H), 7.68-7.50 (m, 2H), 7.50-7.42 (m, 2H), 7.40-7.31 (m,1H). HRMS (FAB) [M+H]/z Calc'd 298.1344, found 298.1357. Analyzed with0.3H₂O Calc'd, C (79.34), H (5.19), N (13.88). Found: C (79.14), H(5.08), N (13.84).

Example 27(g) 6-indol-4-yl-3-E-styryl-1H-indazole

Example 27(g) was prepared in a similar manner to that described forExample 27(a), except that 4-indoleboronic acid was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, MeOH-d₄) δ 8.25 (d, 1H,J=8.5 Hz), 7.85 (s, 1H), 7.75-7.67 (m, 3H), 7.67-7.52 (m, 2H), 7.52-7.42(m, 3H), 7.39-7.22 (m, 4H), 6.72 (d, 1H, J=3.2 Hz). HRMS (FAB) [M+H]/zCalc'd 336.1501, found 336.1506. Analyzed with 0.3H₂O Calc'd, C (78.97),H (5.36), N (12.01). Found: C (78.95), H (5.20), N (12.03).

Example 27(h) 6-[3-ethoxy-4-hydroxyphenyl]-3-E-styryl-1H-indazole

Example 27(h) was prepared in a similar manner to that described forExample 27(a), except that 3-ethoxy-4-(2-trimethylsilanyl-ethoxymethoxy)benzene boronic acid was used insteadof phenylboronic acid in step (i). ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d,1H, J=8.7 Hz), 7.74 (s, 1H), 7.74-7.16 (m, 10H), 7.07 (d, 1H, J=8.15Hz), 4.27 (q, 2H, J=14.0 Hz), 1.54 (t, 3H, J=14.0 Hz). HRMS (FAB)[M+H]/z Calc'd 357.1603, found 357.1611. Analyzed with 0.2H₂O, Calc'd, C(76.73), H (5.71), N (7.78). Found: C (76.72), H (5.91), N (7.63).Starting material was prepared as follows:

4-Bromo-2-ethoxy-phenol (Smith et al., Soc. Pl., 1877-78 (1992)) wasconverted to 3-ethoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-benzeneboronic acid in a manner similar to that described for Example 24(a)steps (vi)-(vii). ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H, J=8.0 Hz), 7.72(s, 1H), 7.31 (d, 1H, J=8.1 Hz), 5.37 (s, 2H), 4.29 (q, 2H, J=14.0 Hz),3.87 (t, 2H, J=16.8 Hz), 1.54 (t, 2H, J=14.0 Hz), 0.99 (t, 2H, J=16.8Hz), 0.03 (s, 9H).

Example 27(i)6-[3-(2-hydroxyethoxy)-4-hydroxyphenyl]-3-E-styryl-1H-indazole

Example 27(i) was prepared in a similar manner to that described forExample 27(a), except that3-[2-(trimethylsilanyl-ethoxymethoxy)ethoxy](2-trimethylsilanyl-ethoxymethoxy)-benzeneboronic acid, prepared from 2-(2-hydroxy-ethoxy)-phenol (Yamaguchi etal., Bull. Chem. Soc. Jpn., 61, 2047-54 (1988)) in a similar manner tothat described in Example 24(c) steps (i)-(iii) and was used instead ofphenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d, 1H,J=8.7 Hz), 7.73-7.17 (m, 1H), 6.92 (d, 1H. 1=8.2 Hz), 4.13 (t, 2H, J=9.7Hz), 3.8 (t, 2H, 1=9.7 Hz). HRMS (FAB) [M+H]/z Calc'd 373.1552, found373.1563. Analyzed with 0.05 trifluoroacetic acid, Calc'd, C (73.37), H(5.35), N (7.41). Found: C (73.11), H (5.33), N (7.39).

Example 27(j) 6-(3,4-dimethoxyphenyl)-3-E-styryl-1H-indazole

Example 27(j) was prepared in a similar manner to that described forExample 27(a), except that 3,4-dimethoxyphenylboronic acid was usedinstead of phenylboronic acid in step (i). ¹H NMR (300 MHz, DMSO-d₆) δ8.01 (d, 1H, J=8.1 Hz), 7.51-7.05 (m, 1H), 6.86 (d, 1H, J-4.0 Hz) 3.58(s, 3H), 3.65 (s, 3H). HRMS (FAB) [M+H]/z Calc'd 357.1598, found357.1508. Analyzed with 0.2H₂O, Calc'd, C (76.73), H (5.71), N (7.78).Found: C (76.45), H (5.70), N (7.68).

Example 27(k) 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole

6-(22-methoxypyridin-5-yl)-3-(((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas converted to 6-(2-methoxypyridin-5-yl)-3-E-styryl-1H-indazole in asimilar manner to that described for Example 27(a). ¹H NMR (300 MHz,CDCl₃) □8.53 (d, 1H, J=2.1 Hz), 8.15 (d, 1H, J-9.2 Hz), 7.97 (dd, 1H,1=2.6, 8.6 Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J=8.6 Hz).HRMS (FAB) [M+H]/z Calc'd 328.1450, found 328.1462. Anal. Calc'd, C(77.04), H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65).The starting material was prepared as follows:

A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol),hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh₃)₄ (0.28 g, 0.24 mmol)in degassed dioxane (10 ml) was refluxed under for 16 h.6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanylthoxymethyl)-1H-indazole(2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh₃)₄(0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. Themixture was then diluted with ethyl acetate (150 ml), and washed withbrine (30 ml). The organics were dried over MgSO₄, then concentratedunder reduced pressure. Purification by silica gel chromatography gave6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazoleas a yellow solid (1.12 g, 40%). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (d, 1H,J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69(s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03(s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, 1=8.3 Hz), −0.03 (s, 9H).

Example 28(a) 6-(3-hydroxyphenyl)-3-E-styryl-1H-indazole

A solution of 100 mg (0.3 mmol)63-methoxyphenyl)-3-E-styryl-1H-indazole, from Example 27(b), was cooledto −78° C. and treated with BBr₃ (1.8 ml of a 1M solution in CH₂Cl₂, 1.8mmol). The resulting solution was held at −78° C. for 15 min, thenwarmed to 0° C., and held 3 h. A solution of saturated aqueous sodiumbicarbonate was then added (10 ml), followed by ethyl acetate (50 ml).The organic layer was washed with brine (20 ml), then concentrated underreduced pressure. Purification by silica gel chromatography gave6-(3-hydroxyphenyl)-3-E-styryl-1H-indazole as a white solid (55 mg,59%). ¹H NMR (300 MHz, MEOH-d₄) δ 8.16 (d, 1H, 1=8.5 Hz), 7.71-7.62 (m,3H), 7.61-7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.33-7.25 (m, 2H), 7.20-7.10(m, 2H), 6.85-6.79 (m, 1H); δ 13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H,1=8.4 Hz), 7.73 (d, 2H, J=7.3), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H),7.33-7.25 (m, 1H), 6.89 (d, 2H, J=8.6 Hz).

Example 28(b) 6-(4-hydroxyphenyl)-3-E-styryl-1H-indazole

6-(4-methoxyphenyl)-3-E-styryl-1H-indazole, from Example 27(c), wasconverted to 6-(4-hydroxyphenyl)-3-E-styryl-1H-indazole in a similarmanner to that described for Example 28(a). ¹H NMR (300 MHz, DMSO-d₆) δ13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.73 (d, 2H, 3=7.3Hz), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d,2H, J=8.6 Hz). HRMS (FAB) [M+Na]/z Calc'd 313.1341, found 313.1347.Analyzed with 0.5H₂O Calc'd, C (78.48), H (5.33), N (8.72). Found: C(78.35), H (5.26), N (8.49).

Example 28(c) 6-(2-hydroxypyridin-5-yl)-3-E-styryl-1H-indazole

6-(2-Methoxypyridin-5-yl)-3-E-styryl-1H-indazole indazole, from Example27(k), was converted to 6-(2-hydroxypyridin-5-yl)-3-E-styryl-1H-indazolein a similar manner to that described for Example 28(a). ¹H NMR (300MHz, DMSO-d₆) δ 8.22 (d, 1H, J=8.4 Hz), 7.96 (dd, 1H, J=2.6, 9.65 Hz),7.81 (d, 1H, J=2.0 Hz), 7.74-7.30 (m, 9H), 6.50 (d, 1H, J=9.4 Hz). HRMS(FAB) [M+H]/z Calc'd 314.1293, found 314.1280. Analyzed with 0.1trifluoroacetic acid, Calc'd, C (72.69), H (4.86), N (12.59). Found: C(72.77), H (4.81), N (12.65).

Example 28(d) 6-(3,4-dihydroxyphenyl)-3-E-styryl-1H-indazole

6-(3,4-Dimethoxyphenyl)-3-E-styryl-1H-indazole, from Example 27( ), wasconverted 6-(3,4-dihydroxyphenyl)-3-E-styryl-1H-indazole in a similarmanner to that described for Example 28(a). ¹H NMR (300 MHz, DMSO-d₆) δ9.09 (br s, 1H), 9.07 (br s, 1H), 8.20 (d, 1H, J=85), 7.73 (d, 2H, J=7.5Hz), 7.56 (d, 2H, J=10.1 Hz), 7.53 (s, 1H), 7.43-7.29 (m, 4H), 7.11 (s,1H), 7.04 (d, 1H, J=8.2 Hz), 6.86 (d, 1H, J=8.2 Hz). HRMS (FAB) [M+H]/zCalc'd 329.1290, found 329.1274. Analyzed with 1.0H₂O, Calc'd, C(66.79), H (4.73), N (7.15). Found: C (66.54), H (4.56), N (7.36).

Example 29(a)6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1H-indazole

6-Pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolewas converted to6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1H-indazole in asimilar manner to that described for Example 27(a). ¹H NMR (300 MHz,CDCl₃) 513.55 (s, 1H), 8.68 (dd, 2H, J=4.6, 1.6 Hz), 8.21 (d, 1H, J=8.5Hz), 7.96 (s, 1H), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.66 (dd, 1H, J₁=8.5,1.4 Hz), 7.58 (d, 2H, J=8.0 Hz), 7.51 (s, 2H), 7.39-7.32 (m, 1H). MS(FAB) [M+H]/z Calc'd 366, found 366. Analyzed with 0.7H₂O Calc'd, C(63.40), H (3.83), N (11.09). Found: C (63.63), H (3.75), N (10.83).The starting material was prepared as follows:

2,6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed with triethylphosphite (1.66 g, 10 mmol) and heated at 150° C. for 2 h. The resultingmixture was then distilled at 160° C. under reduced pressure (10 mm Hg)to remove the excess triethyl phosphite.(2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as acolorless liquid (1.46 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.28 (m,2H), 7.15-7.07 (m, 1H), 4.144.02 (m, 4H), 3.60 (d, 2H, J=22.4 Hz), 1.27(t, 6H, J=7.0 Hz).

Ozone gas was bubbled through a solution of6-pyrid-4-yl-3-E-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(2.13 g, 5.0 mmol) in THF (25 ml) and MeOH (25 ml) at −78° C. for 15min. Argon was then bubbled through the solution for 10 min at −78° C.for 10 min, then dimethyl sulfide (1.46 ml, 20 mmol) was added. Thesolution was allowed to warm to rt, and held for 2 h. The solution waspoured into brine (300 ml), then extracted with ethyl acetate (3×100ml). The organics were dried over MgSO₄, then evaporated under reducedpressure. Purification by silica gel chromatography gave6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydeas a white solid (2.2 g, 75%). ¹H NMR (300 MHz, CDCl₃) δ 10.39 (s, 1H),8.75 (d, 2H, J=1.6 Hz), 8.45 (d, 1H, J=2.8 Hz), 7.91 (s, 1H), 7.75-7.66(m, 3H), 5.90 (s, 2H), 3.63 (t, 2H, J=2.7 Hz), 0.93 (t, 2H, J=2.8 Hz),0.00 (s, 9H).

A solution of (2,6-dichlorobenzyl)phosphinic acid diethyl ester (582 mg,2.0 mmol) in DMF (15 ml) was cooled to 0° C. and treated with NaH (160mg of 60% in mineral oil, 4.0 mmol). The resulting solution was held at0° C. for 30 min, then treated with 6pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(353 mg, 1.0 mmol). The resulting solution was allowed to warm to rtover 1 h, then held at rt 2 h. The solution was poured into brine (250ml), then extracted with ethyl acetate (3×80 ml). The organics weredried over MgSO₄, then concentrated under reduced pressure. Purificationby silica gel chromatography gave6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a yellow oil (330 mg, 67%). ¹H NMR (300 MHz, CDCl₃) δ 7.72 (dd, 2H,J=4.6, 1.5 Hz), 8.16 (d, 1H, J=8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H,J=4.5, 1.6 Hz), 7.60 (s, 2H), 7.56 (dd, 1H, J=8.5, 1.5 Hz), 7.39 (d, 1H,J=8.1 Hz), 7.18-7.12 (m, 1H), 3.64 (t, 2H, J=8.3 Hz), 0.92 (t, 2H, J=8.3Hz), 0.00 (s, 9H).

Example 29(b) 6-pyridyl-4-yl-3-E-[2-(3-methylphenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to the desired product in a similar manner to thatdescribed for Example 29(a). ¹H NMR (300 MHz, MeOH-d₄) 8.88 (d, 1H,J=6.7 Hz), 8.41-8.35 (m, 3H), 8.16 (s, 1H), 7.80 (dd, 1H, J=8.6, 1.6Hz), 7.67-7.48 (m, 4H), 7.35 (t, 1H, J=7.6 Hz), 7.22-7.17 (m, 1H), 4.88(s, 3H). MS (FAB) [M+H]/z Calc'd 312, found 312. Analyzed with 0.2H₂₀,1.1 trifluoroacetic acid Calc'd, C (63.27), H (4.23), N (9.54). Found: C(63.08), H (4.18), N (9.80).

Example 29(c) 6-pyrid-4-yl-3-E-[2-(4-chlorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to the desred product in a similar manner to thatdescribed for Example 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H),8.67 (dd, 2H, J=4.6, 1.6 Hz), 8.33 (d, 1H, J=8.5 Hz), 7.92 (s, 1H), 7.81(dd, 2H, J=4.6, 1.6 Hz), 7.78 (d, 2H, J=8.5 Hz), 7.67-7.56 (m, 3H), 7.46(d, 2H, J=8.5 Hz). Analyzed with 0.15H₂O, Calc'd, C (71.81), H (4.31), N(12.56). Found: C (71.85), H (4.26), N (12.48).

Example 29(d) 6-pyrid-4-yl-3-E-[2-(biphenyl-4-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(d) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.68 (d, 2H,J=4.6, 1.5 Hz), 8.35 (d, 1H, J=8.5 Hz), 7.93 (s, 1H), 7.87-7.79 (m, 4H),7.73 (d, 4H, J=8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m, 2H), 7.41-7.34 (m,1H). MS (FAB) [M+H]/z Calc'd 374, found 374. Analyzed with 0.20H₂OCalc'd, C (82.82), H (5.19), N (11.15). Found: C (82.82), H (5.19), N(11.16).

Example 29(e)6-pyridyl-4-yl-3-E-[2-(3-methoxyphenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1_(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(e) in a similar manner to that described forExample ²9(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.67 (d, 2H,J=5.3 Hz), 8.33 (d, 2H, J=8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J=4.6,1.5 Hz), 7.65-7.54 (m, 3H), 7.35-7.28 (m, 3H), 3.83 (s, 3H). MS (FAB)[M+H]/z Calc'd 328, found 328. Analyzed with 0.20H₂O Calc'd, C (76.20),H (5.30), N (12.70). Found: C (76.17), H (5.34), N (12.65).

Example 29(f) 6-pyrid-4-yl-3-E-[2-(pyrid-2-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(f) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, 2H, J=4.5, 1.6 Hz),8.62 (d, 1H, J=3.8 Hz), 8.33 (d, 1H, J=8.5 Hz), 7.99 (d, 1H, J=16.4 Hz),7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.73-7.57 (m, 3H), 7.32-7.26 (m, 1H).Analyzed with 0.05H₂O Calc'd, C (76.26), H (4.75), N (18.72). Found: C(76.22), H (4.79), N (18.76).

Example 29(g) 6-pyrid-4-yl-3-E-[2-(3-fluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole-3-carbaldehyde was converted to Example 29(g) in a similarmanner to that described for Example 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ13.40 (s, 1H), 8.68 (dd, 2H, J=4.5, 1.6 Hz), 8.34 (d. 1H, J=8.4 Hz),7.92 (s, 1H), 7.81 (dd, 2H, J1=4.5, 1.6 Hz), 7.74-7.52 (m, 5H),7.49-7.40 (m, 1H), 7.1&7.07 (m, 1H). MS (FAB) [M+H]/z Calc'd 316, found316. Anal. Calc'd, C (76.17), H (4.48), N (13.33). Found: C (76.07), H(4.53), N (13.36).

Example 29(h) 6-pyrid-4-yl-3-E-[2-(2-fluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(h) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 8.66 (dd, 2H,J=4.5, 1.6 Hz), 8.23 (d, 1H, 3=8.2 Hz), 7.98-7.90 (m, 2H), 7.80 (dd, 2H,J=4.5, 1.7 Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, 1H), 7.30-7.21 (m, 2H).MS (FAB) [M+H]/z Calc'd 316, found 316. Anal. Calc'd, C (76.17), H(4.48), N (13.33). Found: C (76.12), H (4.51), N (13.29).

Example 29(i) 6-pyrid-4-yl-3-E-[2-(3-chlorophenyl)ethenyl]-1H-indazole

6-Pyridinyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(i) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 8.68 (dd, 2H,J=4.5, 1.6 Hz), 8.35 (d, 1H, 3=8.1 Hz), 7.92 (s, 1H), 7.86 (s, 1H), 7.82(dd, 2H, J=4.5, 1.7 Hz), 7.74-7.51 (m, 4H), 7.43 (t, 1H, J=7.8 Hz),7.37-7.21 (m, 1H). MS (FAB) [M+H]/z Calc'd 332, found 332. Anal. Calc'd,C (72.40), H (4.25), N (12.67). Found: C (72.52), H (4.28), N (12.57).

Example 29(j)6-pyrid-4-yl-3-E-[2-(2-methylthiazol-4-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 290) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (s, 1H), 8.67 (dd, 2H,J=4.5, 1.6 Hz), 8.25 (d, 1H, J=8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H,J=4.5, 1.6 Hz), 7.70-7.50 (m, 4H), 2.72 (s, 3H). MS (FAB) [M+H]/z Calc'd319, found 319. Analyzed with 0.15 trifluoroacetic acid, Calc'd, C(65.51), H (4.25), N (16.70). Found: C (65.56), H (4.37), N 16.53).

Example 29(k) 6-pyrid-4-yl-3-E-[2-(naphthalen-2-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(k) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.68 (dd, 2H,J=4.6, 1.4 Hz), 8.39 (d, 1H, J=8.5 Hz), 8.17 (s, 1H), 8.09-7.89 (m, 8H),7.83 (dd, 2H, J=4.6, 1.6 Hz), 7.74 (s, 2H), 7.65 (dd, 1H, J=8.5, 1.4Hz), 7.60-7.46 (m, 4H). MS (FAB) [M+H]/z Calc'd 348, found 348. Analyzedwith 1.05 trifluoroacetic acid, Calc'd, C (67.10), H (3.89), N (9.00).Found: C (67.20), H (3.93), N (9.05).

Example 29(l)6-pyrid-4-yl-3-E-[2-(2,3-difluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(1) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, CDCl₃+MeOH-d₄) δ 8.68 (d, 2H, J=5.6Hz,), 8.02 (d, 1H, J=85 Hz), 7.70 (s, 1H), 7.58 (dd, 2H, J-4.8, 1.5 Hz),7.57-7.39 (m, 3H), 7.38-7.31 (m, 1H), 7.06-6.96 (m, 2H). MS (FAB)[M+H]/z Calc'd 334, found 334. Analyzed with 0.80H₂O, Calc'd, C (69.08),H (4.23), N (12.08). Found: C (68.77), H (3.93), N (11.85).

Example 29(m)6-pyrid-4-yl-3-E-[2-(3,5-difluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(m) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d₄) δ 8.69 (d, 2H, J=6.3 Hz), 8.34(d, 1H, J=8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H, J=6.3 Hz), 7.71 (d, 1H,J=10.0 Hz), 7.62 (s 1H), 7.60 (s, 1H), 7.36 (d, 1H, J=11.11), 6.95-6.89(m, 1H). MS (ES) [M+H]/z Calc'd 334, found 334. Anal. Calc'd, C (72.06),H (3.93), N (12.61). Found: C (72.20), H (4.01), N (12.58).

Example 29(n) 6-pyrid-4-yl-3-E-[2-(biphenyl-3-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(n) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (d, 2H, J=6.1 Hz), 8.39(d, 1H, J=8.5), 8.04 (s, 1H), 7.92 (s, 1H), 7.82 (d, 2H, J=6.2 Hz),7.79-7.37 (m, 1 H). MS (ES) [M+H/z Calc'd 374, found 374. Anal. Calc'd,C (83.62), H (5.13), N (11.25). Found: C (83.47), H (5.08), N (11.32).

Example 29(o)6-pyrid-4-yl-3-E-[2-(2,6-difluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(o) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d₄) δ 8.69 (d, 2H, J=6.3 Hz), 8.21(d, 1H, J=8.6 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J=6.3 Hz), 7.83 (d, 1H,1-17.1 Hz), 7.71 (1H, J=8.6 Hz), 7.65 (d, 1H, J=17.1 Hz), 7.40-7.35 (m,1H), 7.13-7.08 (m, 2H). MS (ES) [M+H]/z Calc'd 334, found 334. Analyzedwith 0.1H₂O, Calc'd, C (71.67), H (3.97), N (12.54). Found: C (71.37), H(3.90), N (12.31).

Example 29(p) 6-pyrid4-yl-3-E-[2-(3-trifluoromethoxyphenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(p) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (d, 2H, 3=6.4 Hz), 8.43(d, 1H, J=8.5 Hz), 8.19 (d, 2H, J=6.4 Hz), 8.07 (s, 1H), 7.81-7.27 (m,5H), 7.78 (s, 1H). MS (ES) [M+H]/z Calc'd 382, found 382. Analyzed with1.0 trifluoroacetic acid, Calc'd, C (55.76), H (3.05), N (8.48). Found:C (55.84), H (3.09), N (8.45).

Example 29(q)6-pyrid-4-yl-3-E-[2-(benzimidazol-2-yl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(q) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, 2H, J=6.1 Hz), 8.25(d, 1H, J=8.5 Hz), 8.03 (d, 1H, J=16.7 Hz), 7.97 (s, 1H), 7.84 (d, 2H,J=6.2), 7.72 (d, 1H, J=8.5 Hz), 7.60-7.57 (m, 2H), 7.53 (d, 1H, J=16.7Hz), 7.22-7.19 (m, 2H). MS (ES) [M+H]/z Calc'd 338, f338. Analyzed with2.0 trifluoroacetic acid, 0.2H₂O, Calc'd, C (52.77), H (3.08), N(12.31). Found: C (52.59), H (3.17), N (12.18).

Example 29(r)6-pyrid-4-yl-3-E-[2-(3,4-methylenedioxyphenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29r in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d, 2H, J=6.1 Hz), 8.30(d, 1H, J=8.5 Hz), 7.89 (s, 1H), 7.81 (d, 2H, J=6.1 Hz), 7.61 (d, 1H,J=9.9 Hz), 7.46-7.42 (m, 3H), 7.18 (d, 1H, J=9.6 Hz), 6.95 (d, 1H, 8.0Hz), 6.05 (s, 2H). MS (ES) [M+H]/z Calc'd 342, found 342. Anal. Calc'd,C (73.89), H (4.43), N (12.31). Found: C (73.74), H (4.52), N (12.40).

Example 29(s)6-pyrid-4-yl-3-E-[2-(2,5-difluorophenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(s) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d₄) δ 8.53 (d, 2H, 1=6.0 Hz), 8.03(d, 1H, J=8.5 Hz), 7.60 (d, 2H, 1=6.2 Hz), 7.56-7.35 (m, 3H), 7.34-7.26(m, 1H), 7.03-6.93 (m, 1H), 6.90-6.81 (m, 1H). MS (ES) [M+H]/z Calc'd334, found 334. Analyzed with 0.30H₂O, Calc'd, C (70.91), H (4.05), N(12.37). Found: C (70.97), H (4.17), N (12.37).

Example 29(t) 6-pyrid-4-yl-3-E-[2-(1H-pyrrol-2-yl)ethenyl]-1H-indazole

Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(t) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d₄) δ 8.60 (d, 2H, J=6.3 Hz), 8.13(d, 1H, J=8.5 Hz), 7.86 (s<, 1H), 7.79 (d, 2H, J=6.2 Hz), 7.57 (dd, 1H,J1=8.5 Hz, J2=1.5 Hz), 7.40 (d, 1H, J=16.8 Hz), 7.09 (d, 1H, J=16.7 Hz),6.87-6.82 (m, 1H), 6.40-6.35 (m, 1H), 6.16 (t, 1H, J=2.9 Hz). MS (ES)[M+H]l/z Calc'd 287, found 287. Analyzed with 0.5 ethyl acetate, 0.3tetrahydrofuran, 0.1 hexanes, 0.1 ethylene diamine, Calc'd, C (72.07), H(6.21), N (16.05). Found: C (71.95), H (6.20), N (15.76).The starting material was prepared as follows:

-   (i) A solution of 1H-pyrrole-2-carbaldehyde (9.5 g, 100 mmol) and    THF (500 ml) was cooled with an ice bath. Bu^(t)ONa (19.2 g, 200    mmol) was added and reaction mixture was stirred at 0° C. for 1 h.    MtsCl (32.7 g, 150 mmol) was then added. The reaction mixture was    allowed to warm to rt and held for 2 h at rt. The solution was then    treated with saturated aqueous NH₄Cl (100 ml) and the mixture was    poured into brine (2 L). The mixture was extraced with EtOAc (3×300    ml). The combined organic layer was dried over MgSO₄ and    concentrated under reduced pressure. The resulting oil was purified    by silica gel chromatography to yield    1-(2,4,6-trimethyl-benzenesulfonyl)1H-pyrrole-2-carbaldehyde as a    light yellow oil (15.7 g, 57%). ¹H NMR (CDCl₃) δ 9.50 (s, 1H),    7.79-7.74 (m, 1H), 7.12 (dd, 1H, J=3.7, 1.8 Hz), 6.95 (s, 2H), 6.38    (t, 1H, J=3.4 Hz), 2.50 (s, 6H), 2.30 (s, 3H).-   (ii) 1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrole-2-carbaldehyde    (2.77 g, 10 mmol) in THF (100 ml) was treated with LiBH₄ (0.44 g, 20    mmol) at rt. The resulting solution was held at rt for 1 h. MeOH    (10 ml) was then added, and the resulting mixture mixture was poured    into brine (600 ml), and extracted with EtOAc (3×200 ml). The    combined organic layer was dried over MgSO₄ and concentrated under    reduced pressure. The resulting oil was then purified on silica gel    column to yield    [1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol as a    light brown oil (2.43 g, 87%). ¹H NMR (CDCl₃) δ 7.17 (dd, 1H, J=3.3,    1.8 Hz), 6.99 (s, 2H), 6.28-6.23 (m, 1H), 6.18 (t, 1H, J=3.3 Hz),    4.42 (s, 2H), 250 (s, 6H), 2.30 (s, 3H).-   (iii) A solution of [1-(2, 4,6-Trimethyl-benzenesulfonyl    1H-pyrrol-2-yl]-methanol (1.4 g, 5.0 mmol) in CHCl₃ (25 ml) was    cooled with an ice bath. SOCl₂ (1.1 ml, 15 mmol) was added slowly.    The solution was allowed to warm to rt, and held an additional 45    min. The solution was then concentrated under reduced pressure.    2-Chloromethyl-1-(2, 4,6-trimethyl-benzenesulfonyl)1H-pyrrole was    obtained as a brown solid (15 g, 100%). ¹H NMR (CDCl₃) δ 7.28 (dd,    1H, J=3.3, 1.7 Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H,    J=3.4 Hz), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).

Example 29(u)6-pyrid-4-yl-3-E-[2-(3-methylcarbamoylmethoxyphenyl)ethenyl]-1H-indazole

6-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehydewas converted to Example 29(u) in a similar manner to that described forExample 29(a). ¹H NMR (300 MHz, MeOH-d₄) δ 8.68 (d, 2H, J=5.9 Hz), 8.51(br s, 1H), 8.37 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 7.93 (s, 1H), 7.87 (d,1H, J=7.7 Hz), 7.85 (d, 2H, J=6.1 Hz), 7.62 (d, 1H, J=8.1 Hz),7.65-7.63(m, 3H), 7.51 (t, 1H, J=7.6 Hz). MS (ES) [M+H]/z Calc'd 355,found 355. Analyzed with 0.4 trifluoroacetic acid, 0.50H₂O, Calc'd, C(69.67), H (4.98), N (14.26). Found: C (69.78), H (5.18), N (14.08).

Example 30(a)6-[3-benzamidophenoxy]-3-E-[2-(thien-2-yl)ethenyl]-1H-indazole

Example 30(a) was prepared in a manner similar to example 6(a) exceptthat (E)-3-thiophen-2-yl-acryloyl chloride was used in place of3-(4-chlorophenyl)acryloyl chloride in step (i). ¹H NMR (DMSO-d₆) δ13.05 (s, 1H), 10.33 (s, 1H), 8.19 (d, 1H, J=8.8 Hz), 7.92 (d, 2H, J=6.9Hz), 7.70 (d, 1H, J=16.5 Hz), 7.65-7.49 (m, 6H), 7.40 (t, 1H, J=8.1 Hz),7.35 (s, 1H, with fine splitting), 7.20 (d, 1H, J=16.5 Hz), 7.10 (m,1H), 7.04 (s, 1H), 6.98 (d, 1H, J=8.8 Hz), 6.86 (s, 1H, J=9.8 Hz). Anal.Calc for C₂₆H₁₉N₃O₂S 0.6H₂O: C, 69.65; H, 4.54; N, 9.37; S, 7.15. Found:C, 69.77; H, 4.45; N, 9.52; S, 7.02.

Example 30(b)6-[3-(1-acetylpiperidin-4-ylcarboxamido)phenoxy]-3-E-[2-(4-chlorophenyl)ethenyl]-1H-indazole

Example 30(b) was prepared in a similar manner to that described for6(a) except that 1-acetyl-piperidine-4-carboxylic acid and HATU was usedin place of benzoyl chloride in step(ii). ¹H NMR (DMSO-d₆) (J=8.6 Hz) δ7.76, (d, J=8.6 Hz), 7.53 (d, l=6.2 Hz), 7.46 (d, J=8.4 Hz), 7.37 (m,3H), 7.01 (s, 1H, with fine splitting), 6.97 (d, J=8.8 Hz), 6.78 (d,J=7.7 Hz), 4.38 (m, 1H), 3.85 (m, 1H), 3.09-2.96 (m, 1H), 2.58 (m, 2H),1.99 (s, 3H), 1.77 (m, 2H), 1.55 (m, 1H), 1.37 (m, 1H). Anal. Calc forC₂₉H₂₇ClN₄O₃.1.3H₂O: C, 64.69; H, 5.54; N, 10.41. Found: C, 64.64; H,5.51; N, 10.23.

Example 30(c)6-[3-benzamidophenoxy]-3-E-[2(fur-2-yl)ethenyl]-1H-indazole

Example 30(c) was prepared in a manner similar to example 6(a) exceptthat (E)-3-furan-2-yl-acryloyl chloride, prepared according to Collect,Czech. Chem. Comm., 52, 409-24 (1987), was used in place of3-(4-chlorophenyl)-acryloyl chloride in step (i). ¹H NMR (DMSO-4) δ13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, J=8.8 Hz), 7.91 (d, 2H, J=7.0Hz), 7.73 (s, 1H), 7.70-7.51 (m, 5H), 7.40 (t, 1H, J=8.4 Hz), 7.30 (AB,2H, J=16.7 Hz), 7.04 (s, 1H), 6.98 (d, 1H, J=8.7 Hz), 6.86 (d, 1H, J=8.0Hz), 6.65 (s, 1H, with fine splitting), 6.60 (s, 1H, with finesplitting). Anal. Calc for C₂₆H₁₉N₃O₂ 0.7H₂O: C, 71.94; H, 4.74; N,9.68. Found: C, 72.17; H, 4.83; N, 9.44.

Example 30(d) 6-[3-(indol-4-ylcarboxamido)phenoxy]-3-E-stryrylindazole

Example 30(d) was prepared in a similar manner to that described forExample 30(a) using 3-(styryl-1H-indazol-6-yloxy)phenylamine in place of3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)phenylamine and1H-indole-4-carboxylic acid in place of benzoic acid in step (ii). ¹HNMR (DMSO-d₆) δ 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H), 8.22 (d,1H, J=8.7 Hz), 7.72-7.38 (m, 10H), 7.30 (d, 1H, J=7.1 Hz), 7.19 (m, 2H),7.04 (m, 3H), 6.82 (m, 2H). Anal. Calc for C₃₀H₂₂N₄O₂ 0.6H₂O: C, 74.86;H. 4.86; N, 11.64. Found: C, 74.90; H, 5.01; N, 11.33.

Example 30(e)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxyl]-3-E-stryrylindazole

Example 30(e) was prepared in a similar manner to that described forExample 30(a) using 3-(styryl-1H-indazol-6-yloxy)-phenylamine in placeof 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)phenylamine and1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid in place of benzoic acidin step (ii).

Example 31(a)6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

To a stirred solution of6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-4,5-dihydro-1H-indazole(492 mg, 1.13 mmol) in 15 mL of 1,4-dioxane was added 386 mg (1.7 mmol)2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mixturewas stirred for 30 min at room temperature, then poured into sat NaHCO₃solution and EtOAc. Layers were separated and the aqueous layer wasre-extracted with EtOAc. The combined organic layers were washedsequentially with sat NaHCO₃ solution and sat NaCl solution, dried overMgSO₄ and conc. under reduced pressure. The residue was flashchromatographed on silica gel eluting CH₂Cl₂/EtOAc: MEOH (1:1:0.1). Theoil obtained was triturated from EtOAc/hexanes to give the titlecompound as a tan solid (420 mg, 86%). ¹H NMR (DMSO-d₆) δ 13.12 (s, 1H),10.30 (s, 1H), 8.60 (d, 1H, J=3.8 Hz), 8.22 (d, 1H, J=8.8 Hz), 7.93 (m,3H), 7.82 (t, 1H, J=7.7 Hz), 7.68-7.49 (m, 7H), 7.40 (t, 1H, J=8.1 Hz),7.27 (m, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 7.03 (d, 1H, J=8.7 Hz), 6.87(d, 1H, J=8.1 Hz, with fine splitting). Anal. Calc for C₂₇H₂₀N₄O₂ 0.65EtOAc: C, 72.59; H, 5.19; N, 11.44. Found: C, 72.34; H, 5.11; N, 11.82.The starting material was prepared as follows:

A solution of 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone(4.00 g, 10.9 mmol) in 20 mL of THF was added slowly to a ˜78° C.solution of LiHMDS (36 mL of 10M solution in THF). Fifteen minutes afteraddition was complete, (E)-3-pyridin-2-yl-acryloyl chloridehydrochloride was added and stirring was continued at −78° C. for 30min. The reaction was quenched with sat. NH₄Cl solution and extractedwith EtOAc (3×). The combined organic layers were washed with sat NaClsolution, dried over MgSO₄ and conc. under reduced pressure. The residuewas flash chromatographed on silica gel eluting Hexanes/EtOAc (2:1). Theappropriate fractions were concentrated under reduced pressure anddissolved in EtOH/HOAc (1:1, 8 ml). To this solution at 80° C. was addedhydrazine hydrate (3.4 ml, 70.0 mmol). After 15 min, all startingmaterial was gone and the reaction mixture was cautiously poured intosat NaHCO₃ and extracted with EtOAc (2×). The combined organic layerswere washed with sat NaCl solution, dried over MgSO₄ and conc. underreduced pressure. The residue was flash chromatographed on silica geleluting CH₂Cl₂/MeOH (9:1) to give6-(3-aminophenoxy)-3-E-[2-(pyridin-2-yl)ethenyl]4,5-dihydro-1H-indazole(676 mg, 19%). ¹H NMR (DMSO-d₆) δ 12.51 (s, 1H), 8.57 (d, 1H, J=3.8 Hz),7.78 (t, 1H, J=7.8 Hz), 7.51 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.35(d, 1H, J=7.9 Hz, with fine splitting), 6.32 (t, 1H, J=2.1 Hz), 6.23 (d,1H, J=7.9 Hz), 5.54 (s, 1H), 5.23 (s, 2H), 2.95 (t, 2H, J=8.2 Hz), 2.60(t, 2H, J=8.2 Hz); MS [m+H]/z Calc'd 331. Found: 331. Anal. Calc forC₂₀H₁₈N₄O 0.15H₂O: C, 72.12; H, 5.54; N, 16.82. Found: C, 72.11; H,5.55; N, 16.61.

To a stirred solution of the dihydro aniline (350 mg, 1.06 mmol) andbenzoic acid (776 mg, 6.36 mmol) in 15 mL of DMF, was added HATU (2.42g, 6.36 mmol) and NEt₃ (1.8 ml, 12.71 mmol). The reaction mixture washeated at 50° C. for 1.5 hr, cooled and poured into ice/sat NaClsolution. The ppt was collected by vacuum filtration, washed with H₂Oand air dried. To this filter cake dissolved in 10 mL of MeOH/THF (1:1),was added K₂CO₃ (650 mg) and 1 mL of H₂O. After 1 hr, the reactionmixture was poured into sat NaCl solution and extracted with EtOAc (2×).The combined organic layers were washed with sat NaCl solution, driedover MgSO₄ and conc. under reduced pressure. The residue was flashchromatographed on silica gel eluting CH₂Cl₂/EtOAc/MeOH (1:1:0.1) togive6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]4,5-dihydro-1H-indazole(333 mg, 72%). ¹H NMR (DMSO-d₆) δ 12.58 (bs, 1H), 10.34 (s, 1H), 8.57(d, 1H, J=3.8 Hz), 7.95 (d, 2H, J=6.8 Hz), 7.81-7.70 (m, 2H), 7.63-7.50(m, 6H), 7.40 (t, 1H, J=8.1 Hz), 7.25 (m, 1H), 7.09 (d, 1H, J=16.3 Hz),6.89 (d, 1H, J=8.0 Hz), 5.64 (s, 1H), 2.99 (t, 2H, J=8.1 Hz), 2.66 (t,2H, J=8.1 Hz). Anal. Calc for C₂₇H₂₂N₄O₂ 0.1 CH₂Cl₂: C, 73.48; H, 5.05;N, 12.65. Found: C, 73.48; H, 5.05; N, 12.48.

Example 31(b)6-[3((1,5-Dimethyl-1H-pyrazol-3-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 31(b) was prepared in a similar manner to that described forExample 31(a) except that 1,5-dimethyl-1H-pyrazole-3 carboxylic acid wasused in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 13.13 (s,1H), 10.07 (s, 1H), 8.60 (d, 1H, J=4.3 Hz), 8.21 (d, 1H, J=8.7 Hz), 7.93(d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.4 Hz), 7.69-(m, 3H), 7.56 (d, 1H,J=16.3 Hz), 7.32 (m, 2H), 7.05 (s, 1H), 7.01 (d, 1H, J=8.7 Hz), 6.80 (m,1H), 6.52 (s, 1H), 3.81 (s, 3H) 2.29 (s, 3H). Anal. Calc forC₆H₂₂N₆O₂.0.1 CH₂Cl₂/0.1 hexanes: C, 6858; H, 5.09; N, 17.97. Found: C,68.26; H, 5.25; N, 17.61.

Example 31(c)6-[3-((5-methylsulfonylthien-2-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 31(c) was prepared in a similar manner to that described forExample 31(a) except that 5-methanesulfonyl-thiophene-2-carboxylic acidwas used in place of benzoic acid in step (ii). ¹H NMR (DMSO d) δ 13.17(s, 1H), 10.58 (s, 1H), 8.61 (d, 1H, J=4.0 Hz), 8.24 (d, 1H, J=8.8 Hz),8.05 (d, 1H, J=4.1 Hz), 7.97-7.79 (m, 3H), 7.68 (d, 1H, J=7.8 Hz),7.60-7.48 (m, 3H), 7.43 (t, 1H, J=8.2 Hz), 7.28 (m, 1H), 7.10 (s, 1H,with fine splitting), 7.00 (d, 1H, J=8.7 Hz), 6.92 (d, 1H, J=8.1 Hz,with fine splitting), 3.41 (s, 3H). Anal. Calc for C₂₆H₂₀N₄O₄S₂ 0.4EtOAc: C, 60.07; H, 4.24; N, 10.15; S, 11.62. Found: C, 60.22; H, 4.48;N. 10.05; S, 11.49.

Example 31(d)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2(pyridin-2-yl)ethenyl]-1H-indazole

Example 31(d) was prepared in a similar manner to that described forExample 31(a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acidwas used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 13.15(s, 1H), 10.18 (s, 1H), 8.61 (d, 1H, J=3.7 Hz), 8.22 (d, 1H, 1=8.8 Hz),7.94 (d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.5 Hz), 7.67 (d, 1H, J=7.7 Hz),7.55 (m, 3H), 7.40 (t, 1H, J=8.1 Hz), 7.28 (m, 1H), 7.06 (s, 1H), 7.01(d, 1H, J=8.8 Hz), 6.89 (d, 1H, J=7.9 Hz), 6.78 (s, 1H), 4.38 (q, 2H,J=7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J=7.1 Hz). Anal. Calc forC₂H₂₄N₆O₂ 0.6 EtOAc: C, 68.25; H, 5.61; N, 16.24. Found: C, 68.28; H,5.88; N, 16.01.

Example 31(e)6-[3-(1-Methylimidazol-2-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 31(e) was prepared in a similar manner to that described forExample 31(a) except that 1-methyl-1H-imidazole-2-carboxylic acid wasused in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 13.13 (s,1H), 10.47 (s, 1H), 8.60 (d, 1H, J=3.9 Hz), 8.21 (d, 1H, J=8.7 Hz), 7.93(d, 1H, J=16.3 Hz), 7.82 (t, 1H, J=7.6 Hz), 7.65 (m, 3H), 7.56 (d, 1H,J=16.3 Hz), 7.43 (s, 1H), 7.37 (t, 1H, J=8.1 Hz), 7.28 (m, 1H), 7.04 (m,3H), 6.84 (d, 1H, J=7.7 Hz), 3.95 (s, 3H). Anal. Calc forC₂₅H₂₀N₆O₂.0.4H₂O: C, 67.49; H, 4.80; N, 18.65. Found:C, 67.68; H. 4.73;N. 18.94.

Example 31(f)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethenyl]-1H-indazole

Example 31(f) was prepared in a similar manner to that described forExample 31(a) except that (E)-3-(1,2-dimethyl-H-imidazol-4-yl)acryloylchloride hydrochloride was used in place of (E)-3-pyridin-2-yl-acryloylchloride hydrochloride in step (i) and1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used in place ofbenzoic acid in step (ii). ¹H NMR (DMSO-d₆) & 12.82 (s, 1H), 10.17 (s,1H), 8.05 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.38(t, 1H, J=8.1 Hz), 7.25 (s, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 6.92 (d,1H, J=8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 6.78 (s, 1H), 4.37 (q, 2H, J=7.0Hz), 3.56 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J=7.0 Hz).Anal. Calc for C₂₇H₂₇N₇O₂ 1.0H₂O.0.3 EtOAc: C, 64.39; H, 6.02; N, 18.64.Found; C, 64.52; H, 5.98; N, 18.52.

Example 32(a)6-[3-benzamidophenoxy]-3-E-[2-(1H-imidazol-4-yl)ethenyl]-1H-indazole

To a stirred solution of the6-(3-benzamidophenoxy)-3-E-[2-(1-(2-trimethylsilanyl-ethoxy)-methyl-imidazol-4-yl)ethenyl]-1H-indazolecompound (213 mg, 0.39 mmol) in 5 mL of THF was added 1.0 M TBAF in THF(6.0 ml, 6.0 mmol) and ethylenediamine (0.26 ml, 3.86 mmol). Afterheating at 70° C. for 18 h, the reaction mixture was cooled, dilutedwith EtOAc, and washed repeatedly with sat NaHCO₃ solution. The organiclayer was dried over MgSO₄ and conc. under reduced pressure. The residuewas flash chromatographed on silica gel eluting CH₂Cl₂:EtOAc: MeOH(1:1:0.2). The oil obtained was triturated from EtOAc/hexanes to giveAG13853 (65 mg, 40%). ¹H NMR (DMSO-d₆) δ 12.90 (s, 1H), 12.35 (s, 1H),10.32 (s, 1H), 8.08 (d, 1H, J=8.7 Hz), 7.91 (d, 2H, J=6.8 Hz), 7.81 (s,1H), 7.67.49 (m, 5H), 7.42-7.31 (m, 4H), 7.03 (s, 1H), 6.96 (d, 1H,J=8.7 Hz), 6.85 (d, 1H, J=8.1 Hz). Anal. Calc for C₂₅H₁₉N₅O₂.0.7H₂O.0.4EtOAc: C, 68.07; H, 5.07; N, 14.92. Found: C, 67.93; H, 4.89; N, 15.06.

The starting material was prepared in a similar manner to that desribedfor Example 31(a) except that(E)-3-{1-(2-trimethylsilanyl)-ethoxymethyl)-1H-imidazol-4-yl]-acryloylchloride hydrochloride was used in place of (E)-3-pyridin-2-yl-acryloylchloride hydrochloride in step (i).

Example 32(b)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1H-imidazol-4-yl)ethenyl]-1H-indazole

Example 32(b) was prepared in a similar manner to that described forExample 32(a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acidwas used in place of benzoic acid in step (ii). ¹H NMR (DMSO-d₆) δ 12.89(s, 1H), 12.37 (s, 1H), 10.18 (s, 1H), 8.07 (d, 1H, J=8.9 Hz), 7.74 (s,1H), 7.58 (d, 1H, J=8.3 Hz), 7.49 (s. 1H), 7.44-7.32 (m, 3H), 7.28 (s,1H), 7.01 (s, 1H), 6.95 (d, 1H, J=8.9 Hz), 6.86 (d, 1H, J=8.6 Hz), 6.78(s, 1H), 4.38 (q, 2H, J=7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J=, 7.1 Hz).Anal. Calc for C₂₅H₂₃N₇O₂.0.8H₂O.0.1 EtOAc: C, 63.99; H, 5.37; N, 20.57.Found: C, 63.72; H, 5.12; N, 20.25.

Example 32(c)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(2-methylimidazol-4-yl)ethenyl]-1H-indazole

Example 32(c) was prepared in a simialr manner to that described for32(b) except that(E)-3-[2-methyl-1-(2-trimethylsilanyl)ethoxymethyl)-1H-imidazol-4-yl]-acryloylchloride hydrochloride was used in place of(E)-3-[1-(2-trimethylsilanyl)-ethoxymethyl)-1H-imidazol-4-yl]-acryloylchloride hydrochloride in step (i). ¹H NMR (DMSO-d₆) δ 12.85 (bs, 1H),11.80 (bs, 1H), 10.18 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.58 (d, 1H,J=8.4 Hz), 7.48 (s, 1H), 7.39 (t, 1H, J=8.2 Hz), 7.33-7.05 (m, 3H), 7.00(s, 1H), 6.93 (d, 1H, J=8.7 Hz), 6.86 (d, 1H, J=8.2 Hz), 6.78 (s, 1H),4.38 (q, 2H, J=7.1 Hz), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J=7.1Hz). Anal. Calc for C₂₆H₂₅N₇O₂.0.9H₂O.0.4 EtOAc: C, 63.87; H, 5.83; N,18.89. Found: C, 63.64; H, 5.76; N, 18.85.

Example 33(a)6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole

Example 33(a) was prepared from6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazolein a similar manner to that described for Example 11. R_(f) sm 0.8, p0.15 (ethyl acetate); ¹H NMR (300 MHz, dmso-d6) δ 13.45 (s, 1H), 8.72(d, 1H, J=3.9 Hz), 8.47 (m, 1H), 8.31 (d, 1H, J=8.5 Hz), 8.06 (d, 1H,J=16.4 Hz), 7.92 (dt, 1H, J=1.7, 7.6 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.71(s, 1H), 7.68 (d, 1H, J=16.5 Hz), 7.61 (dd, 1H, J=1.7, 7.2 Hz),7.45-7.36 (m, 3H), 7.31 (d, 1H, J=8.5 Hz), 7.17 (m, 1H), 2.89 (d, 3H,J=4.6 Hz); ¹³C NMR (75 MHz, dmso-d6) δ 167.8, 154.8, 149.5, 141.9,141.8, 137.0, 136.8, 135.4, 132.5, 130.2, 130.0, 129.2, 127.7, 126.1,125.4, 123.5, 122.5, 122.4, 121.6, 120.2, 114.5; LCMS (100% area) Rt=3.5min (pos) [M+H]/z Calc'd 387, found 387. Analyzed with 0.1H₂O, 0.1 EtOAcCalc'd, C (67.78), H (4.82), N (14.11), S (8.08). Found: C (67.78), H(4.77), N (14.06), S (8.08).The starting material was prepared as follows:

Under argon,6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (30.0g, 62.9 mmol) prepared in Example 14, step (i), was dissolved indichloromethane (375 mL) and was cooled to −42° C. in an acetonitile-dryice bath. Ozone was then bubbled through the mix (1 L/min, 60 V, 1.8Amps) for 45 min. Standard indicators did not give a clear color changedue to the solutions background color. To avoid over-oxidation, thereactions progress was monitored by TLC (1:9 EtOAc-Hex). The ozoneaddition was stopped and the flask was flushed with argon. Dimethylsulfide (30 mL) was then added and the mixture was allowed to warm to23° C. This mixture was stirred for 4 h and was concentrated underreduced pressure. The oil was placed under high vacuum for 16 h. Theresidue was dissolved in dichloromethane (15 mL) and was diluted withhexane (100 mL) to give some crystals (not desired product). The mixturewas filtered and the filtrate was concentrated. The residue wasdissolved in 8:2 Hex-EtOAc (250 mL), treated with 50 mL silica,filtered, and concentrated. 6Iodo-3-carboxaldehyde-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazoleformed as a yellow solid after 72 h under high vacuum (24.17 g, −95%pure by NMR, 91% yield): R_(f) sm 0.34, p 0.29 (ethyl acetate-hexane1:9); ¹H NMR (300 MHz, CDCl₃) δ 10.25 (s, 1H), 8.09 (s, 1H), 8.05 (d,1H), 7.80 (d, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 0.93 (t, 2H), 0.0 (s,9H).

Iodo-3-carboxaldehyde-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(24.0 g, 59.7 mmol) was dissolved in THF (350 mL) and was cooled to −5°C. To this was added solid 2-picolyltriphenylphosphoniumchloride-potassium hydride (45.7 g, 100 mmol, 1.68 equiv). The reactionmixture was allowed to stir for 45 min. To the mixture, was added 3N HCl(20 mL) followed by saturated aqueous sodium bicarbonate (50 mL) to givea pH of 6. Excess THF was removed under reduced pressure and the residuewas partitioned between ethyl acetate and water. The organics werewashed with saturated aqueous sodium bicarbonate, water and the organiclayer was separated, dried over sodium sulfate, decanted andconcentrated under reduced pressure. The residue was taken up in 1:9ethyl acetate-hexane and was filtered. The filtrate was purified bysilica gel chromatography (2 L silica, 20 to 30 to 50% ethylacetate-hexane) to give6-Iodo-3-E-[2-(pyridin-2-yl)ethenyl-1-[2-trimethyl-silanly)-ethoxymethyl]-1H-indazole(18.9 g, 66% yield): R_(f) sm 0.52, p 0.25 (ethyl acetate-hexane 2:8);¹H NMR (300 MHz, CDCl₃) δ 8.64 (m, 1H), 8.00 (d, 1H, 3=0.7 Hz), 7.87 (d,1H, J=16.4 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.69 (td, 1H, J=7.7, 1.8 Hz),7.55 (d, 1H, J=16.4 Hz), 7.55 (dd, 1H, J=8.5, 1.3 Hz), 7.47 (d, 1H,J=7.9 Hz), 7.18 (dd, 1H, J=1.1, 4.8 Hz), 5.70 (s, 2H), 359 (t, 2H, J=8.2Hz), 0.90 (t, 2H, J=8.2 Hz), −0.04 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ156.8, 151.2, 144.2, 143.6, 138.0, 132.3, 132.2, 124.4, 124.0, 123.8,123.7, 123.5, 120.7, 94.1, 79.4, 68.1, 19.17, 0.0.

In a 200 mL round bottom flask was weighed cesium carbonate (13.7 g,41.9 mmol, 2.5 equiv) and this salt was dried under high vacuum with aheat gun. The catalyst [Pd(dppf)Cl₂—CH₂Cl₂] (1.37 g, 1.68 mmol, 0.1equiv) and6-Iodo-3-E-[2-(pyridin-2-yl)ethenyl-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(8.0 g, 16.76 mmol) were then added and the mix was taken up in DMF (71mL). To this mixture was added methyl thiosalicylate (4.62 mL, 33.5mmol, 2.0 equiv) and the vessel was warmed to 85° C. for 4.5 h. Thismixture was cooled to 23° C., was partitioned between ethyl acetate (350mL) and 50%-saturated aqueous sodium bicarbonate (300 mL). The organicswere washed with 10% sodium bisulfite (200 mL), brine and the organiclayer was separated. The organic material was dried over sodium sulfate,decanted and concentrated under reduced pressure. Purification by silicagel chromatography (500 mL silica; 30 to 40 to 50% ethyl acetate-hexane)gave6-[(2-methoxycarbonylphenyl)sulfanyl-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole(6.44 g, 74%): R_(f) sm 0.52, p 0.19 (ethyl acetate-hexane 3:7); FTIR(thin film) 2950, 2887, 2356, 1713, 1585, 1464, 1433, 1250, 1076, 837cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, 1H), 8.12 (d, 1H), 8.04 (d,1H), 7.99 (d, 1H, J=16.4 Hz), 7.90 (s, 1H), 7.88 (t, 1H), 7.76 (d, 1H,J=16.4 Hz), 7.62 (d, 1H), 7.55 (d, 1H), 7.30-7.15 (m, 3H), 6.92 (d, 1H),5.80 (s, 2H), 4.01 (s, 3H), 3.78 (t, 2H), 0.96 (t, 2H), −0.03 (s, 9H);¹³C NMR (75 MHz, CDCl₃) δ 168.3, 156.8, 151.2, 144.3, 144.2, 143.2,138.0, 133.8, 133.6, 132.5, 132.4, 129.9, 129.3, 128.5, 126.0, 124.7,124.6, 123.8, 123.5, 118.3, 79.4, 68.2, 53.7, 19.2, 0.0; LCMS (100%area) Rt=4.4 min, (pos) [M+H]/z Calc'd 518.2, found 518.2.

To6-[(2-methoxycarbonylphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole(8.50 g, 16.4 mmol) was added THF (120 mL), methanol (120 ml), water(120 mL) and potassium carbonate (15.9 g, 115 mmol, 7.0 equiv). Thismixture was heated to 67° C. and was stirred for 22 h. The mixture wascooled and the excess solvents were removed. The residue was partitionedbetween ethyl acetate (300 mL) and water (250 mL). The aqueous wasacidified with 20% citric acid to pH 5 (−70 mL) and the aqueous wasdrained. The organic layer was washed with water (50 mL) and hexane (100mL) was added to help precipitate the crystals that were forming in theethyl acetate layer. The solid was filtered and dried to give6-[(2-carboxyphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxy-methyl]-1H-indazole(7.56 g, 91%): R_(f) sm 0.67, p 0.41 (ethyl acetate-hexane 8:2); ¹H NMR(300 MHz, CDCl₃) δ 8.60 (m, 1H), 8.10 (d, 1H, J=8.4 Hz), 8.04 (dd, 1H,J=1.7, 7.7 Hz), 7.85 (d, 1H, J=16.5 Hz), 7.83 (s, 1H), 7.70 (dt, 1H,J=1.7, 7.7 Hz), 7.59 (d, 1H, J=16.5 Hz), 7.52 (d, 1H, J=7.9 Hz), 7.38(dd, 1H, J=1.3, 8.4 Hz), 7.22-7.10 (m, 3H), 6.80 (dd, 1H, J=1.0, 8.0Hz), 3.59 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.8.1 Hz), −0.1 (s, 9H).

6-[(2-Carboxyphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole(820 mg, 1.63 mmol) was dissolved in DMF (5 mL) and was treated withmethyl amine (2M in THF, 4.1 mL, 8.13 mmol, 50 equiv) and with HATU (929mg, 2.44 mmol, 1.5 equiv). This mixture was stirred for 30 min, waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate and the organic layer was separated. The organic materialwas dried over sodium sulfate, decanted and concentrated under reducedpressure. Purification by silica gel chromatography (50 mL silica; 60 to70% ethyl acetate-hexane) gave6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazoleas a solid (795 mg, 94%): R_(f) sm 0.35, p 0.23 (ethyl acetate-hexane6:4); FTIR (thin film) 3306, 2951, 1643, 1606, 1587, 1563, 1469, 1433,1410, 1303, 1249, 1217, 1075, 836 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.70(m, 1H), 8.06 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=16.3 Hz), 7.74 (dt, 1H,J=1.8, 7.7 Hz), 7.70-7.60 (m, 3H), 752 (d, 1H, J=7.9 Hz), 7.35-7.20 (m,5H), 6.45 (bs, 1H), 5.80 (s, 2H), 3.62 (t, 2H), 3.00 (d, 3H), 0.93 (t,2H), −0.05 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 179.7, 169.9, 156.8,151.1, 144.2, 143.0, 138.1, 136.1, 135.4, 133.2, 132.2, 132.1, 130.2,1285, 127.2, 124.7, 124.1, 123.8, 123.5, 123.3, 114.9, 68.1, 28.2, 19.2,0.00; LCMS (100% area) Rt=4.15 min, (pos) [M+H]/z Calc'd 517.2, found517.2

Example 33(b)6-[2-(2-methylquinol-6-ylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 33(b) was prepared in a similar manner to that described forExample 33(a) except that, in step (v), 6-amino-2-methylquinoline wasused instead of methylamine: ¹H NMR (300 MHz, CDCl₃) δ 10.2 (bs, 1H),8.64 (m, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.98-7.80 (m, 4H), 7.69 (dt,1H, J=1.7, 7.7 Hz), 7.55-7.40 (m, 7H), 7.25-7.16 (m, 3H), 2.71 (s, 3H).

Example 33(c)6-[2-(phenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 33(c) was prepared in a similar manner to that described forExample 33(a) except that, in step (v), aniline was used instead ofmethyl amine: ¹H NMR (300 MHz, dmso-d6) δ 13.35 (s, 1H), 10.53 (s, 1H),8.67 (m, 1H), 8.22 (d, 1H, J=7.5 Hz), 7.99 (d, 1H, J=16.4 Hz), 7.85 (dt,1H, J=1.8, 7.6 Hz), 7.80-7.55 (m, 5H), 7.45-7.10 (m, 9H); LCMS (100%area) Rt=3.86, (pos) [M+H]/z Calc'd 449.1, found 449.1. Analyzed with0.41H₂O Calc'd, C (71.13), H (4.60), N (12.29), S (7.03). Found: C(71.04), H (4.62), N (12.31), S (7.01).

Example 33(d)6-[2-(3-chlorophenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 33(d) was prepared in a similar manner to that described forExample 33(a) except that, in step (v), 3-chloroaniline was used insteadof methyl amine: ¹H NMR (300 MHz, CDCl₃) δ 8.53 (m, 1H), 7.92 (d, 1H,J=8.4 Hz), 7.77 (d, 1H, J=16.4 Hz), 7.68 (dt, 1H, J=1.7, 7.7 Hz),7.64-7.56 (m, 2H), 7.51-7.43 (m, 3H), 7.35-7.28 (m, 4H), 7.19-7.12 (m,3H), 7.02 (m, 1H); LCMS (100% area) Rt 3.98 min, (pos) [M+H]/z Calc'd483.1, found 483.1. Analyzed with 0.3H₂O Calc'd, C (66.40), H (4.05), N(11.47), S (6.57). Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 33(e)6-[2-(cyclopropylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H—1H-indazole

Example 33(e) was prepared in a similar manner to that described forExample 33(a) except that, in step (v), cyclopropylamine was usedinstead of methylamine: ¹H NMR (300 MHz, dmso-d6) δ 13.45 (s, 1H), 8.73(d, 1H, J=3.9 Hz), 8.56 (d, 1H, J=4.3 Hz), 8.31 (d, 1H, J=8.5 Hz), 8.08(d, 1H, J=16.4 Hz), 7.91 (dt, 1H, J=1.7, 7.7 Hz), 7.78 (d, 1H, J=7.8Hz), 7.70 (m, 2H), 7.57 (m, 1H,), 7.40 (m, 3H), 7.30 (d, 1H, J=8.4 Hz),7.20 (d, 1H, J=7.8 Hz), 2.94 (m, 1H), 0.80 (m, 2H), 0.65 (m, 2H); LCMS(100% area) Rt 3.51 min, (pos) [M+H]/z Calc'd 413.1, found 413.1.

Example 33(f)6-[2-(2,2,2-trifluoroethylcarbamoyl)phenylsulfanyl]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazole

Example 33(f) was prepared in a similar manner to that described forExample 33(a) except that, in step (v), 2,2,2-trifluoroethylamine wasused instead of methylamine: ¹H NMR (300 MHz, dmso-d6) δ 13.5 (s, 1H),9.29 (t, 1H, J=6.3 Hz), 8.74 (m, 1H), 8.37 (d, 1H, J=8.3 Hz), 8.10 (d,1H, J=16.4 Hz), 7.94 (dt, 1H, J=1.8, 7.6 Hz), 7.80 (d, 1H, J=7.9 Hz),7.75-7.65 (m, 3H), 7.55-7.40 (m, 3H), 7.33 (d, 1H), 7.22 (d, 1H), 4.22(m, 2H); LCMS (100% area) Rt=3.70 min, (pos) [M+H]/z Calc'd 455.1, found455.1.

Example 33(g)6-[2-(carboxy)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H—1H-indazole,tetrabutylammonium salt

Example 33(g) was prepared in a similar manner to that described forExample 33(a) except that step (v) was omitted: R_(f) sm 0.41, p 0.0(ethyl acetate-hexane 8:2); ¹H NMR (300 MHz, dmso-d6) δ 8.75 (m, 1H),8.25 (d, 1H, J=8.6 Hz), 8.05 (d, 1H, 16.4 Hz), 7.88 (dt, 1H, J=1.8, 7.8Hz), 7.83-7.60 (m, 4H), 7.33 (m, 2H), 7.16 (m, 2H), 6.70 (m, 1H), 3.30(m, 8H), 1.70 (m, 8H), 1.42 (m, 8H), 1.05 (t, 12H); LCMS (100% area) Rt3.24 (pos) [M+H (acid component only)]/z Calc'd 374.1, found 374.1.Analyzed with 0.1H₂O Calc'd, C (72.07), H (8.21). N (9.09), S (5.20).Found: C (72.04), H (8.29), N (9.06). S (5.12).

Example 33(h)6-[2-(3-chlorophenylcarbamoyl)phenylsulfanyl]-3-Z-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 33(h) was prepared in the same reaction as Example 33(d). Itshould be noted that, although this compound was isolated andcharacterized pure, it was found to isomerize to Example 33(d) underassay conditions. ¹H NMR (300 MHz, CDCl₃) δ 8.82 (m, 1H), 8.31 (s, 1H),7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, J=2.0 Hz), 7.46 (d, 1H, J=8.0Hz), 7.33 (m, 5H), 7.21 (t, 1H, J=8.0 Hz), 7.13 (dd, 1H, J=1.5, 8.1 Hz),7.08 (m, 1H), 6.98 (d, 1H, J=13.0 Hz), 6.66 (d, 1H, J=13.1 Hz); LCMS(100% area) Rt 4.40 min, (pos) [M+H]/z Calc'd 483.1, found 483.1.Analyzed with 0.3H₂O Calc'd, C (66.40), H (4.05), N (11.47), S (6.57).Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 346-[2-((RS-(trans-2-phenylcyclopropyl)carbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 33(g) was converted to Example 34 in a similar manner to thatdescribed for Example 33(a), step (v) except thattrans-2-phenylcyclopropylamine was used instead of methylamine: FTIR(thin film) 1704, 1638, 1584, 1559, 1530, 1497, 1460, 1430, 1339, 1306,1269, 1223, 1152, 1086, 1061, 966, 844 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ13.3 (s. 1H), 8.71 (d, 1H, J=4.4 Hz), 8.61 (d, 1H, J=3.9 Hz), 8.20 (d,1H, J=8.5 Hz), 7.96 (d, 1H, J=16.4 Hz), 7.81 (dt, 1H, J=1.7, 7.6 HZ),7.66 (d, 1H, J=7.8 Hz), 7.59-7.50 (m, 3H), 7.37-7.25 (m, 5H), 7.21-7.08(m, 5H), 3.01 (m. 1H), 2.03 (m, 1H), 1.25 (m, 2H); LCMS (100% area)Rt=3.72 min. (pos) [M+H]/z Calc'd 489.2, found 489.2. Analyzed with 0.6MeOH, 0.16 CH₂Cl₂ Calc'd, C (70.86), H (5.17), N (10.75), S (6.15).Found: C (70.87), H (5.18), N (10.75), S (5.96).

Example 35(a)6-[2(n-Propylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-1H-indazole

6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl)-1H—indazole(60 mg, 0.1112 mmol) was dissolved in DMF (0.8 mL), treated withn-propylamine (11 μL., 0.1335 mmol) and stiffed at room temperature.HPLC analysis after 15 minutes indicated that all staring material hadbeen consumed. The reaction mixture was concentrated by high vacuumrotary evaporation, giving a solid. The solid was sonicated with CH₂Cl₂giving a fine suspension, which was filtered, and rinsed with CH₂Cl₂ toprovide 40 mg (87% yield) of the title compound. ¹H NMR (DMSO-d₆) δ13.31 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.41 (t, J=6.2 Hz, 1H), 8.19 (d,J=8.5 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (t,J=8.7 Hz, 1H), 7.56 (m, 2H), 7.47 (m, 1H), 7.30 (m, 3H), 7.18 (d, f=8.3Hz, 1H), 3.20 (q, J=6.0 Hz, 2H), 1.55 (septet, J=5.9 Hz, 2H), 0.92 (t,J=6.0 Hz, 3H). Anal. Calcd. for C₂₄H₂₂N₄OS-(1.5H₂O, 0.8 DMF): C, 63.41;H, 6.17; N, 13.45; S, 6.41. Found: C, 63.37; H, 5.68; N, 13.44; S, 6.32.The starting material was prepared as follows:

A solution of the tetrabutyl ammonium salt of6-(2-carboxyphenylsulfanyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole)(615 mg, 1.0 mmol) dissolved in dry DMF (10.0 ml) was treated withpyridine (89 μL, 1.1 mmol), and pentafluorophenyl trifluoroacetate (206μL, 1.2 eq), at room temperature, under an argon atmosphere. HPLCanalysis after 45 minutes showed mostly unreacted carboxylic acid, soadditional pyridine (89 μL, 1.1 mmol), and pentafluorophenyltrifluoroacetate (206 μL, 1.2 eq) were added. HPLC analysis 15 minuteslater indicated that starting acid had been completely consumed. Thereaction mixture was concentrated under high vacuum rotary evaporation,then triturated with CH₂Cl₂ (−1 mL) causing the formation of crystals,which were collected by filtration, rinsed with additional CH₂Cl₂, anddried. The mass of the bright yellow crystals was 336 mg. The remainingfiltrate was concentrated and purified by flash chromatography (10%acetontrile/CH₂Cl₂ to 80% acetonitrile/CH₂Cl₂), yielding an additional70 mg of solid. The total yield of6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolewas 406 mg, or 89%. ¹H NMR (CDCl₃) δ 10.22 (1H, bs), 8.66 (1H, d, J=4.5Hz), 8.28 (2H, dd, J=7.7, 1.5 Hz), 8.15 (1H, d, J=8.5 Hz), 7.97 (1H, d,J=16.2 Hz), 7.79 (1H, s), 7.15-7.75 (7H, m), 6.92 (1H, d, J=8.1 Hz).

Example 35(b)6-[2-(i-Propylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(b) was prepared in a similar manner to that described forExample 35(a) except that isopropylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H), 8.60 (d, J=4.5 Hz, 1H),8.26 (d, J=7.34 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.94 (d, J=16.4 Hz,1H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.56 (m, 2H),7.45 (m, 1H), 7.30 (m, 3H), 7.18 (d, J=8.5 Hz, 1H), 7.08 (m, 1H), 4.04(septet, J=7.4 Hz, 1H), 1.15 (d, J=6.6 Hz, 6H). Anal. Calcd. forC₂₄H₂₂N₄OS 1.7H₂O: C, 64.75; H, 5.75; N, 12.59; S, 7.20. Found: C,64.79; H, 5.36; N, 12.74; S, 7.08.

Example 35(c)6-[2-(Cyclobutylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(c) was prepared in a similar manner to that described forExample 35(a) except that cyclobutylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.62 (m, 2H), 8.19 (d,J=8.5 Hz, 1H), 7.94 (m, 2H), 7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.65 (t,J=8.1 Hz, 1H), 7.56 (s, 1H), 7.47 (m, 1H), 7.30(m, 3H), 7.17 (d, J=8.3Hz, 1H), 4.36 (septet, J=8.1 Hz, 1H), 2.22 (m, 2H), 2.03 (m, 2H), 1.67(m, 2H). Anal. Calcd. for C₂₅H₂₂N₄OS.(0.5H₂O, 0.9 DMF): C, 66.36; H,5.89; N, 13.69; S, 6.40. Found: C, 66.21; H, 5.78; N, 13.82; S, 6.36.

Example 35(d)6-(2-Carbamoylphenylsulfanyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(d) was prepared in a similar manner to that described forExample 35(a) except that ammonia was used instead of n-propylamine. ¹HNMR (DMSO-d₆) δ 8.60 (d, J=4.9 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.94 (m,3H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.60 (m, 4H), 7.48 (bs, 1H), 7.25 (m,4H), 7.0 (m, 1H). Anal. Calcd. for C₂₁H₁₆N₄OS.0.25H₂O: C, 66.91; H,4.41; N, 14.86; S, 8.51. Found: C, 66.99; H. 4.40; N, 15.10; S, 8.49.

Example 35(e)6-[2-((1-methylpyrrol-2-ylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(e) was prepared in a similar manner to that described forExample 35(a) except that 1-methylpyrrol-2-ylhydrazide was used insteadof n-propylamine. ¹H NMR (DMSO-d₆) δ 13.34 (s, 1H), 10.25 (s, 1H), 10.05(s, 1H), 8.60 (d, J=4.5 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.95 (d, J=16.2Hz, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (m, 3H), 7.57 (d, J=16.0 Hz,1H), 7.43-7.18 (m, 4H), 7.07 (d, J=7.9 Hz, 1H), 7.00 (d, J=3.4 Hz, 2H),6.07 (t, J=3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd for C₂₇H₂₂N₆O₂S.0.6H₂O: C, 64.17; H, 4.63; N, 16.63; S, 6.34. Found: C, 64.24; H, 4.48; N.16.56; S, 6.28.

Example 35(f)6-[2-((2-fluorobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(f) was prepared in a similar manner to that described forExample 35(a) except that 2-fluorobenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.99(t, J=5.8 Hz, 1H),8.61 (d, J=4.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.94 (d, J=16.2 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.56 (m, 3H), 7.47(t, J=7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, J=5.7 Hz, 2H).Anal. Calcd. for C₂₈H₂₁FN₄OS.0.25H₂O: C, 69.33; H, 4.47; N, 11.55; S,6.61. Found: C, 69.32; H, 4.41; N, 11.58; S, 6.59.

Example 35(g)6-[2-((4-Methoxybenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(g) was prepared in a similar manner to that described forExample 35(a) except that 4-methoxybenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆)δ 13.31 (s, 1H), 8.90 (t, J=5.5 Hz, 1H),8.60(d, J=4.2 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.55 (m, 3H), 7.30(m, 5H), 7.18 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 4.39 (d, J=6.0Hz, 2H), 3.72 (s, 3H). Anal. Calcd. for C₂₉H₂₄N₄O₂S.0.6H₂O: C, 69.19; H,5.05; N, 11.13; S, 6.37. Found: C, 69.12; H, 4.85; N, 11.24; S, 6.35.

Example 35(h)6-[2-((5-Methylfur-2-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(h) was prepared in a similar manner to that described forExample 35(a) except that 5-methylfur-2-yl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.88 (t, J=5.3 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.54 (m, 3H), 7.30(m, 4H), 7.18 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.1 Hz, 3H). Anal. Calcd.for C₂₇H₂₂N₄O₂S_(0.4)H₂O: C, 68.45; H, 4.85; N, 11.83; S, 6.77. Found:C, 68.35; H, 4.80; N, 11.85; S, 6.68.

Example 35(i)6-[2-(Benzyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(i) was prepared in a similar manner to that described forExample 35(a) except that O-benzyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 11.64 (s, 1H), 8.90 (t,J=5.5 Hz, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d,J=16.3 Hz, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H),7.56 (m, 2H), 7.50-7.24 (m, 9H), 7.17 (t, J=8.5 Hz, 2H), 4.94 (s, 2H).Anal. Calcd. for C₂₈H₂₂N₄O₂S-0.8H₂O: C, 68.22; H, 4.83; N, 11.37; S,6.50. Found: C, 68.08; H, 4.65; N, 11.41; S, 6.47.

Example 35(j)6-[2-(Allyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(j) was prepared in a similar manner to that described forExample 35(a) except that O-allyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d,J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.5 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.56 (m, 2H), 7.48-7.24(m, 5H), 7.16 (m, 2H), 6.00 (m, 1H), 5.37 (d, J=18.3 Hz, 1H), 5.27 (d,J=11.3 Hz, 1H), 4.42 (d, J=6.0 Hz, 1H). Anal. Calcd. forC₂₄H₂₀N₄O₂S.(0.2H₂O, 0.2CH₂Cl₂): C, 65.35; H, 4.96; N, 12.10; S, 6.92.Found: C, 65.24; H, 4.50; N, 12.56; S, 7.17.

Example 35(k)6-[2-(Isopropoxycarbamoyl)phenylsulfanyl]-3-E-(2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(k) was prepared in a similar manner to that described forExample 35(a) except that O-isopropyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H), 11.33 (s, 1H), 8.60 (d,J=4.1 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.95 (d, J=16.5 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.55 (m, 2H), 7.48-7.24(m, 4H), 7.17 (d, J=8.3 Hz, 2H), 4.12 (septet, J=5.7 Hz, 1H), 1.21 (d,J=6.2 Hz, 6H. Anal. Calcd. for C₂₄H₂₂N₄O₂S.(0.4H₂O, 0.7 CH ₂Cl₂): C,59.67; H, 4.91; N, 11.27; S, 6.45. Found: C, 59.61; H, 4.81; N, 11.42;S, 6.45.

Example 35(l)6-[2-((4-Aminobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(l) was prepared in a similar manner to that described forExample 35(a) except that 4-aminobenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) 513.31 (s, 1H), 8.78 (t, J=6.0 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.95 (d, J=16.3 Hz, 1H),7.85 (bs, 1H), 7.81 (dt, 1=1.7, 7.5 Hz. 1H), 7.66 (d, J=7.9 Hz, 1H),7.59 (s, 1H), 7.51 (m, 2H), 7.30 (m, 3H), 7.19 (d, J=8.7 Hz, 1H), 7.05(m, 3H), 6.56 (d, J=8.7 Hz, 1H), 6.51 (d, J=8.5 Hz, 2H), 4.29 (d, J=6.0Hz, 2H). Anal. Calcd. for C₂₈H₂₃N₅OS.0.6 H₂O: C, 68.86; H, 4.99; N,14.34; S, 6.57. Found: C, 68.83; N 4.80; N, 14.16; S. 6.52.

Example 35(m)6-[2((Thien-2-ylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(m) was prepared in a similar manner to that described forExample 35(a) except that thien-2-ylhydrazide was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.49 (bs, 1H), 10.64 (s, 1H), 10.47(s, 1H), 8.66 (d, J=4.0 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.08-7.82 (m,5H), 7.66 (m, 3H), 7.39 (m, 3H), 7.24 (m, 2H), 7.09 (d, J=8.1 Hz, 1H),7.00 (d, J=3.4 Hz, 2H), 6.07 (t, J=3.2 Hz, 1H), 3.88 (s, 3H). Anal.Calcd. for C₂₆H₁₉N₅O₂S₂.1.5H₂O: C, 59.52; H, 4.23; N, 13.35; S, 12.22.Found: C, 59.56; H, 4.42; N, 13.33; S, 11.75.

Example 35(n)6-[2-(N²-(pyrid-2-ylhydrazino)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(n) was prepared in a similar manner to that described forExample 35(a) except that 2-hydrazinopyridine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 10.30 (s, 1H), 8.60 (d,J=4.4 Hz, 1H), 8.48 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.09 (d, J=4.9 Hz,1H), 7.94 (d, J=16.4 Hz, 1H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.67 (m,1H), 7.62-7.47 (m, 3H), 7.40 (m, 2H), 7.31-7.12 (m, 3H), 6.73 (m, 2H).Anal. Calcd. for C₂₆ H₂₀N₆OS.0.3 H₂O: C, 66.45; H, 4.42; N, 17.88; S,6.82. Found: C, 66.33; H, 4.50; N, 17.78; S, 6.60.

Example 35(o)6-[2-(N-Hydroxy-N-methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(o) was prepared in a similar manner to that described forExample 35(a) except that N-methyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.24 (s, 1H), 9.94 (s, 1H), 8.60 (d,J=4.0 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.92 (d, J=16.2 Hz, 1H), 7.80(dt,J=1.7, 7.5 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 7.54 (d, J=16.5 Hz, 1H),7.47-7.24 (m, 6H), 7.16 (d, J=8.5 Hz, 1H) 3.24 (bs, 1H). Anal. Calcd.for C₂₂H₁₈N₄O₂S.(0.5H₂O, 0.3 CH₂Cl₂): C, 61.29; H, 4.52; N, 12.82; S,7.34. Found: C, 61.24; H, 4.33; N, 12.67; S, 7.34.

Example 35(p)6-[2-((Pyrid-4-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(p) was prepared in a similar manner to that described forExample 35(a) except that 4-aminomethyl pyridine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (bs, 1H), 9.07 (t, J=6.8 Hz,1H), 8.60 (d, J=4.2 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.19 (d, J=8.7 Hz,1H), 7.95 (d, J=16.4 Hz, 1H), 7.80 (dt, J 1.7, 7.5 Hz, 1H), 7.68-7.52(m, 3H), 7.42 (m, 2H), 7.39-7.31 (m, 3H), 7.27 (m, 1H), 7.20-7.10 (m,2H), 4.48 (d, J=6.2 Hz, 2H).

Example 35(q)6-[2-((2-Methylphenylhydrazido)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(q) was prepared in a similar manner to that described forExample 35(a) except that 2-methylphenyl hydrazide was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.43 (s, 1H), 10.45 (s, 1H), 10.28(s, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.01 (d J=16.6Hz, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.60 (d, J=16.4 Hz,1H), 7.507.22 (m, 8H), 7.07 (d, J=7.7 Hz, 1H), 2.45 (s, 3H).

Example 35(r)6-[2-(methoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(r) was prepared in a similar mariner to that described forExample 35(a) except O-methyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 11.60 (s, 1H), 8.60 (d,J=3.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.56 (m, 2H), 7.47 (dd,J=7.4, 1.7 Hz, 1H), 7.43-7.24 (m, 3H), 7.17 (m, 2H), 3.72 (s, 3H). Anal.Calcd. for C₂₂H₁₈N₄O₂S.0.6 CH₂Cl₂: C, 59.86; H, 4.27; N, 12.36; S. 7.07.Found: C, 59.94; H, 4.40; N, 12.00; S, 6.80.

Example 35(s)6-[2-((Cyclopropyl)methoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(s) was prepared in a similar manner to that described forExample 35(a) except that O-cyclopropyl hydroxylamine was used insteadof n-propylamine. ¹H NMR (DMSO-d₆) δ 13.38 (s, 1H), 11.51 (s, 1H), 8.64(d, J=3.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.00 (d, J=16.4 Hz, 1H), 7.86(m, 2H), 7.63-752 (m, 2H), 7.49-7.29 (m, 4H), 7.17 (m, 2H), 3.70 (d,J=7.2 Hz, 1H), 1.10 (m, 1H), 0.53 (m, 2H), 0.27 (m, 2H). Anal. Calcd.for C₂₅H₂₂N₄O₂S 1.6H₂O: C, 63.70; H, 5.39; N, 11.89; S, 6.80. Found: C,63.58; H, 4.95; N, 11.71; S, 6.66.

Example 35(t)6-[2-(n-Propoxycarbamoyl)phenylsulfanyl]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazole

Example 35(t) was prepared in a similar manner to that described forExample 35(a) except that O-n-propyl hydroxylamine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 11.48 (s, 1H), 8.60 (d,J=3.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 7.81(dt, J=1.7, 7.5 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.60-7.52 (m, 2H),7.49-7.24 (m, 4H), 7.17 (m, 2H), 3.84 (t, J=6.6 Hz, 2H), 1.62 (septet,J=6.4 Hz, 2H), 0.92 (t, J=6.1 Hz, 3H). Anal. Calcd. forC₂₄H₂₂N₄O₂S.(0.5H₂O, 0.25 CH₂Cl₂): C, 63.21; H, 5.14; N, 12.16; S, 6.96.Found: C, 63.15; H, 5.13; N, 12.17; S, 6.99.

Example 35(u)6-[2-(Allylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(u) was prepared in a similar manner to that described forExample 35(a) except that allylamine was used instead of n-propylamine.¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.60 (m, 2H), 8.19 (d, J=8.5 Hz, 1H),7.93 (d, J=16.3 Hz, 3H), 7.79 (dt, J=1.7, 7.5 Hz, 1H), 7.64 (m, 1H),7.60-7.48 (m, 3H), 7.37-7.23 (m, 3H), 7.17 (d, J=8.5 Hz, 1H), 7.07 (m,1H), 5.87 (m, 1H), 5.25 (dq, J=17.33, 1.9 Hz, 1H), 5.09 (dq, J=10.2, 1.9Hz, 1H), 3.87 (m, 2H). Anal. Calcd. for C₂₄H₂₀N₄OS0.8 CH₂Cl₂: C, 62.00;H, 4.53; N, 11.66; S, 6.67. Found: C, 62.08; H, 4.73; N, 11.99; S, 6.66.MALDI FTMS (MH⁺) Calc'd, 413.1431, found 413.1449.

Example 35(v)6-[2-(Cyclopropylmethyl-carbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(v) was prepared in a similar manner to that described forExample 35(a) except that cyclopropylmethyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H), 8.60 (d, J=4.0 Hz, 1H),8.48 (t, J=5.3 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.90 (d, J=16.4 Hz, 1H),7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.67-7.45 (m, 4H), 7.33-7.23 (m, 3H), 7.18(d, J=8.3 Hz, 1H), 7.06 (m, 1H), 3.13 (t, J=6.2 Hz, 2H), 1.00 (m, 1H),0.41 (m, 1H), 0.24 (m, 1H). Anal. Calcd. for C₂₅H₂N₄OS-0.5 CH₂Cl₂: C,65.30; H. 4.94; N, 11.95; S, 6.84. Found: C, 65.10; H. 4.93; N, 12.04;S, 6.82. MALDI FTMS (MH⁺) Calc'd 427.1587, found 427.1605.

Example 35(w)6-[2-(Cyanomethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(w) was prepared in a similar manner to that described forExample 35(a) except that aminoacetonitrile was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.35 (s, 1H), 9.19 (t, J=5.3 Hz, 1H),8.60 (d, J=4.8 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.94 (d, J=16.4 Hz, 3H),7.79 (dt, J=1.7, 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7.41-7.23 (m, 3H), 7.18(d, J=8.5 Hz, 1H), 7.06 (d, J=6.6 Hz, 1H), 4.32 (d, J=5.5 Hz, 2H). MALDIFTMS (MH⁺) Calc'd 412.1227, found 412.1215.

Example 35(x)6-[2-(Ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(x) was prepared in a similar manner to that described forExample 35(a) except that ethylamine was used instead of n-propylamine.¹H NMR (DMSO-d₆) δ 8.60 (d, J=4.0 Hz, 1H), 8.40 (t, J=6.2 Hz, 1H), 8.18(d, J=8.5 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, J=1.7, 7.5 Hz, 1H), 7.68-7.44(m, 3H), 7.56 (m, 2H), 7.30 (m, 3H), 7.17 (dd, J=8.1, 1.8 Hz, 1H), 7.06(m, 1H), 3.24 (m, 2H), 1.11 (t, J=7.0 Hz, 3H). Anal. Calcd. forC₂₃H₂₀N₄OS-(1.75H₂₀, 1.0 DMF): C, 61.82; H, 6.09; N, 13.87; S, 6.35.Found: C, 6158; H, 5.66; N, 13.96; S, 5.93. MALDI FIMS (MH⁺) Calc'd401.1431, found 401.1417.

Example 35(y)6-[2-(Thiazol-2-ylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(y) was prepared in a similar manner to that described forExample 35(a) except that 2-aminothiazole was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.32 (s, 1H), 12.67 (s, 1H), 8.60 (d,J=4.1 Hz, 1H), 8.18 (d, J=85 Hz, 1H), 7.93 (d, J=16.3 Hz, 1H), 7.80 (dt,J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H),7.607.51 (m, 3H), 7.49-7.34 (m, 2H), 7.26 (m, 2H), 7.18 (m, 2H). Anal.Calcd. for C₂₄H₁₇N₅OS₂.0.75H₂O: C, 61.45; H, 3.98; N, 14.93; S, 13.67.Found: C, 61.35; H, 4.10; N, 14.96; S, 13.68.

Example 35(z)6-[2-(2-(Ethoxy)ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(z) was prepared in a similar manner to that described forExample 35(a) except that 2-ethoxyethyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.30 (s, 1H), 8.60 (d, J=4.0 Hz, 1H),8.45 (t, J=6.2 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.93 (m, 2H), 7.80 (dt,J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36-7.23(m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.07 (m, 1H), 3.50 (m, 6H), 1.10 (d,J=7.0 Hz, 3H). Anal. Calcd. for C₂₅H₂₄N₄O₂S-0.5 CH₂Cl₂: C, 62.89; H,5.17; N, 11.50; S, 6.58. Found: C, 62.45; H, 5.33; N, 11.25; S, 6.55.

Example 35(aa)6-[2-((3-methoxybenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(aa) was prepared in a similar manner to that described forExample 35(a) except that 3-methoxybenzyl amine was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) 13.30 (s, 1H), 8.97 (t, J=5.5 Hz, 1H),8.60 (d, J=4.2 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.93 (d, J=16.3 Hz, 1H),7.80 (dt, J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.60-7.51 (m, 3H),7.38-7.15 (m, 5H), 7.08 (m, 1H), 6.94 (m, 2H), 6.80 (dd, J=8.1, 1.5 Hz,1H), 4.44 (d, J=6.6 Hz, 2H), 3.71 (s, 3H). Anal. Calcd. forC₂₉H₂₄N₄O₂S.0.4H₂O: C, 60.25; H, 4.50; N, 17.57; S, 8.04. Found: C,60.14; H, 4.47; N, 17.42; S, 8.00.

Example 35(bb)6-[2-((fur-2-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(bb) was prepared in a similar manner to that described forExample 35(a) except that 2-aminomethyl furan was used instead ofn-propylamine. ¹H NMR (DMSO-d₆) δ 13.31 (s, 1H), 8.93 (t, J=5.7 Hz, 1H),8.60 (d, J=4.3 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.93 (d, 1=16.5 Hz, 1H),7.80 (dt, J=1.9, 7.4 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.59-7.48 (m, 4H),7.30 (m, 4H), 7.37-7.24 (m, 3H), 7.18 (d, J=9.2 Hz, 1H), 7.06 (d, J=8.1Hz, 1H), 6.40 (m, 1H), 6.31 (mp, 1H), 4.44(d, J=5.3 Hz, 2H). Anal.Calcd. or C₂₆H₂₀N₄O₂S.(0.1H₂O, 0.75 CH₂Cl₂): C, 62.02; H, 4.22: N,10.82; S. 6.19. Found: C, 61.58; H, 4.30; N, 10.55; S, 6.12.

Example 35(cc)6-[2-(2-Propynylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(cc) was prepared in a similar manner to that described forExample 35(a) except that propargylamine was used instead of propylamine(76%): ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.96 (d, 1H, J=8.6 Hz),7.81 (d, 1H, 16.4 Hz), 7.68 (dt, 1H, J=1.8, 7.8 Hz), 7.6 (m, 1H),7.52-7.45 (m, 3H), 7.3-7.23 (m, 3H), 7.16 (m, 2H), 4.10 (m, 2), 2.20 (t,1H. J=2.6 Hz). LCMS (100% area) Rt=3.36 min, (pos) [M+H]/z Calc'd 411.1,found 411.1. Analyzed with 0.2H₂O, 0.17 DMF, 1.2 dichloromethane,Calc'd, C (58.44), H (4.19), N (11.05), S (6.07). Found: C (58.18), H(4.11), N (10.98), S (6.05).

Example 35(dd)6-[2-(ethoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(dd) was prepared in a similar manner to that described forExample 35(a) except that ethoxyamine was used instead of propylamine:¹H NMR (300 MHz, CDCl₃) δ 11.60 (s, 1H), 8.71 (d, 1H, J=7.9 Hz), 8.30(d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=16.4 Hz), 7.91 (dt, 1H, J=1.7, 7.7Hz), 7.76 (d, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.56 (dd, 1H, J=1.8, 7.3 Hz),7.52-7.36 (m, 3H), 7.28 (m, 2H)4.06 (q, 2H, j 7.0 Hz), 1.31 (t, 2H,J=7.0 Hz); LCMS (100% area) Rt=3.28 min, (pos) [M+H]/z Calc'd 417.1,found 417.1. Analyzed with 0.2H₂O Calc'd, C (65.53), H (4.98), N(13.05), S (7.48). Found: C (65.66), H (4.91), N (12.75), S (7.44).

Example 35(ee)6-[2-(2-Methyl-2-propenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(ee) was prepared in a similar manner to that described forExample 35(a) except that 2-methylallylamine was used insteadpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.98 (d, 1H, J=85Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, 3=1.7, 7.7 Hz), 7.60 (m,1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H),4.89 (s. 1H), 4.81 (s, 1H), 3.90 (d, 2H, J=5.5 Hz), 1.71 (s, 3H). LCMS(100% area) Rt=3.37 min, (pos) [M+H]/z Calc'd 427.1, found 427.1.Analyzed with 0.7H₂O, 0.1 dichloromethane Calc'd, C (67.35), H (5.31), N(12.52), S (7.16). Found: C (67.55), H (5.39), N (12.35), S (7.15).

Example 35(ff)6[2-((3-Fluorobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(ff) was prepared in a similar manner to that described forExample 35(a) except that 3-fluorobenzylamine was used insteadpropylamine: ¹H NMR (300 MHz, CDCl ₃) δ 8.60 (m, 1H), 7.97 (d, 1H, J=8.5Hz), 7.86 (d, 1H, J=16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H),7.18 (m, 2H), 7.11 (dd, 1H, J=1.6, 8.5 Hz), 6.95 (m, 3H), 4.51 (d, 2H,J=5.7 Hz); LCMS (100% area) Rt=3.55 min, (pos) [M+H]/z Calc'd 481.1,found 481.1. Analyzed with 0.7H₂O, 05 dichloromethane, Calc'd, C(63.91), H (4.40), N (10.46), S (5.99). Found: C (63.80), H (4.34), N(10.34), S (5.98).

Example 35(gg)6-[2-(2-methylamino)ethylcarbamoyl)phenylsufanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(gg) was prepared in a similar manner to that described forExample 35(a) except that N-methylethylenediamine was used instead ofpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.60 (m, 1H), 7.98 (d, 1H, J=8.5Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, J=1.7, 7.7 Hz), 7.52 (m,1H), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 7.16 (m, 2H), 3.45 (t, 2H),2.69 (t, 2H), 2.15 (bs, 3H); LCMS (100% area) Rt=3.16 min, (pos) [M+H]/zCalc'd 430.1, found 430.1. Analyzed with 0.2H₂O, 0.6 dichloromethane,0.06 hex, Calc'd, C (61.28), H (5.24), N (14.31), S (6.55). Found: C(61.26), H (5.14), N (14.22), S (6.56).

Example 35(hh)6-[2-(2-(Thien-2-yl)ethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(hh) was prepared in a similar manner to that described forExample 35(a) except that 2-(2-aminoethyl)thiophene was used insteadpropylamine: ¹H NMR (300 MHz, CDCl₃) δ 8.56 (m, 1H), 7.98 (d, 1H, J=8.5Hz), 7.81 (d, 1H, J=16.4 Hz), 7.69 (dt, 1H, J=1.7, 7.7 Hz), 7.60 (m,1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H),6.63 (m, 1H), 6.52 (m 1H), 3.45 (q, 2H), 3.00 (t, 2H). Analyzed with0.5H₂O, 0.07 dichloromethane Calc'd, C (65.35), H (4.69), N (11.26), S(12.82). Found: C (65.49), H (4.80), N (11.21), S (12.77).

Example 35(ii)6-[2-(aminocarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 35(ii) was prepared in a similar manner to that described forExample 35(a) except that hydrazine was used instead propylamine: ¹H NMR(300 MHz, dmso-d6) □13.3 (s, 1H), 9.57 (s, 1H), 8.54 (d, 1H, J=3.9 z),8.14 (d, 1H, J=8.5 Hz), 7.89 (d, 1H, J=16.4 Hz), 7.73 (dt, 1H, J=1.7,7.6 Hz), 7.60 (d, 1H, J=7.9 Hz), 7.50 (m, 2H), 7.40 (dd, 1H, J=1.8, 7.1Hz), 7.3-7.1 (m, 4H), 7.0 (m, 1H). LCMS (100% area) Rt=0.55 min, (pos)[M+H]l/z Calc'd 388.1, found 388.1. Analyzed with 0.1 DMF, 0.55 EtOAc,0.12 Tol (NMR) and 0.15H₂O Calc'd, C (63.98), H (5.15), N (15.63), S(7.02). Found: C (63.99), H (5.07), N (15.75), S (6.89).

Examples 35(jj)-35(nn) can be prepared in a similar manner to thatdescribed for Example 35(a).

Example 35(jj)

Example 35(kk)

Example 35(ll)

Example 35(mm)

Example 35(nn)

Example 36(a)6-[2-(N²-(1-Methylimidazol-2-ylmethylidene)hydrazino)carbonyl)henylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-1H-indazole

The compound prepared in Example 35(ii) (40 mg, 0.103 mmol) was treatedwith 1-methyl-2-imidazolecarboxaldehyde (29 mg, 0.258 mmol, 25 equiv) inethanol to give Example 36(a): ¹H NMR (300 MHz, dmso-d6) δ 8.60 (m, 2H),8.31 (s, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.80 (m, 2H),7.63 (m, 2H), 7.40 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.02 (m, 2H),6.93 (s, 1H), 4.00 (s, 3H); LCMS (1100% area) Rt=4.0 min, (pos) [M+H]/zCalc'd 480.2, found 480.2. Analyzed with 1.45H₂O Calc'd, C (61.76), H(4.76), N (19.39), S (6.34). Found: C (61.78), H (4.67), N (19.34), S(6.39).

Example 36(b)6-[2-(N²-(pyrid-2-ylmethylidene)hydrazino)carbonyl)-phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 36(b) prepared in a similar manner to that described for Example36(a) except that 2-pyridylcarboxaldehyde was used instead of1-methyl-2-imidazolecarboxaldehyde: ¹H NMR (300 MHz, CDCl₃) δ 8.57 (m,2H), 8.45 (m, 2H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (d, 1H), 7.83 (d,1H), 7.8-7.1 (m, 1H); LCMS (100% area) Rt=4.0 min, (pos) [M+H]/z Calc'd477.1, found 477.1. Analyzed with 0.85H₂O Calc'd, C (65.93), H (4.45), N(17.09), S (6.52). Found: C (66.02), H (4.42), N (16.95), S (6.38).

Example 36(c)6-[2-(N²-(2,2,2-trifluroethylidene)hydrazino)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 36(c) was prepared in a similar manner to that described forExample 36(a) except that trifluoroacetaldehyde was used instead of1-methyl-2-imidazolecarboxaldehyde: ¹H NMR (300 MHz, dmso-d6) δ 8.70 (m,1H), 8.25 (m, 1H), 8.02 (d, 1H), 7.90 (dt, 1H), 7.80-7.20 (m, 10H). LCMS(100% area) Rt=5.64 min, (pos) [M+H]/z Calc'd 468.1, found 468.0.Analyzed with 0.75H₂O Calc'd, C (57.39), H (3.67), N (14.56), S (6.67).Found: C (57.44), H (3.67), N (14.56), S (6.67).

Example 37(a)6-[6-fluoro-2-(ethoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 37(a) was prepared in a similar manner to that described forExample 35(a) except that the starting material described below wasemployed and that ethoxyamine was used instead of propylamine: ¹H NMR(300 MHz, CDCl₃) δ 8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, J=16.4 Hz),7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, J=16.4 Hz), 7.40(t, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (m, 1H), 7.10 (d, 1H), 3.90(q, 2H), 1.19 (t, 3H). LCMS (100% area) Rt=4.85 min, (pos) [M+H]/zCalc'd 435.1, found 435.1, (neg) [M−H]/z Calc'd 433.1, found 433.1.Analyzed with 0.35H₂O, 0.07 EtOAc Calc'd, C (62.56), H (4.57), N(12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11).Starting material was prepared as follows:

A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at23° C. The mixture was stirred under argon for 10 h. The solution wasdiluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid(5 mL). The organic layer was washed with saturated aqueous sodiumbicarbonate, dried over sodium sulfate, decanted and concentrated underreduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester.¹H NMR (300 MHz, CDCl₃)57.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41(q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/zCalc'd 201.0, found 200.9.

The above thioether was prepared in a similar manner to that describedfor Example 33(a), step (iii) except that 3-Fluoro-2-mercapto-benzoicacid ethyl ester was used instead of thiosalicylate (320 mg, 39%): FTIR(thin film) 2952, 1727, 1607, 1586, 1564, 1469, 1433, 1366, 1292, 1249,182, 1141, 1074, 836 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.62 (m, 1H), 7.90(d, 1H, J=8.6 Hz), 7.85 (d, 1H, 3=16.4 Hz), 7.67 (dt, 1H, J=1.8, 7.7Hz), 757-7.38 (m, 5H), 7.23-7.10 (m, 3H), 5.65 (s, 2H), 4.34 (q, 2H,J=7.1 Hz), 3.56 (t, 2H, J=8.2 Hz), 1.30 (t, 3H, J=7.1 Hz), 0.88 (t, 2H,J=8.2 Hz), −0.06 (s, 9H); LCMS (100% area) Rt=4.44 min. (pos) [M+H]/zCalc'd 549.2, found 549.2.

The carboxylic acid above was prepared in a similar manner to thatdescribed for Example 33(a), step (iv) (303 mg, 99%): FTIR (thin film)2953, 2496, 1715, 1643, 1607, 1567, 1470, 1434, 1300, 1250, 1221, 1075,967, 932, 836 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.81 (m, 1H), 7.87 (m,2H), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m, 1H), 4.40 (m, 1H), 7.30 (m,1H), 7.00 (dd, 1H, J=1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t, 2H, J=8.2 Hz),0.93 (t, 2H, J=8.2 Hz), −0.01 (s, 9H). LCMS (100% area) Rt=10.47 min,(pos) [M+H]/z Calc'd 522.2, found 522.2.

The above salt was prepared in a similar manner to that described forExample 33(g): ¹H NMR (300 MHz, dmso-d6) δ 13.2 (s, 1H), 8.68 (m, 1H),8.12 (d, 1H, J=8.5 Hz), 7.98 (d, 1H, J J=16.4 Hz), 7.88 (dt, 1H, J=1.8,7.6 Hz), 7.73 (d, 1H, J=7.9 Hz), 7.61 (d, 1H, J=16.4 Hz), 7.43-7.32 (m,3H), 7.20 (m, 2H), 7.07 (t, 1H), 3.23 (m, 8H), 1.68 (m, 8H), 1.41 (m,8H), 1.04 (t, 12H).

The above pentafluorophenyl ester was prepared in a similar manner tothat described for Example 35(a), step (i): LCMS (100% area) Rt=10.53min, (pos) [M+H]/z Calc'd 558.1, found 558.1.

Example 37(b)6-[6-Fluoro-2-(cyclopropylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 37(b) was prepared in a similar manner to that described forExample 37(a) except that cyclopropylamine was used instead ofethoxyamine: ¹H NMR (300 MHz, dmso-d6) δ 8.42 (m, 1H), 8.28 (d, 1H),7.83 (d, 1H), 7.75 (m, 2H), 7.60 (m, 1H), 7.31 (m, 2H), 7.15 (m, 4H),6.86 (d, 1H), 2.58 (m, 1H), 0.42 (m, 2H), 0.23 (m, 2H). LCMS (100% area)Rt=4.91 min. (pos) [M+H]/z Calc'd 431.1, found 431.1, (neg) M−H]/zCalc'd 429.1, found 429.2. Analyzed with 0.55H₂O Calc'd, C (65.46), H(4.60), N (12.72), S (7.28). Found: C (65.52), H (4.58), N (12.64), S(7.06).

Example 37(c)6-[6-fluoro-2-(isopropoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 37(c) was prepared in a similar manner to that described forExample 37(a) except that isopropoxyamine was used instead ofethoxyamine: ¹H NMR (300 MHz, CDCl₃) δ 9.50 (s, 1H), 8.47 (m, 1H), 7.72(d, 1H), 7.68 (d, 1H, J=16.4 Hz), 7.54 (dt, 1H), 7.35 (m, 4H), 7.20 (m,4H), 4.03 (m, 1H), 1.07 (d, 6H); LCMS (100% area) Rt=4.90 min, (pos)[M+H]/z Calc'd 449.1, found 449.1. Analyzed with 0.1 DMF, 0.3H₂O Calc'd,C (63.28), H (4.87), N (12.45), S (6.95). Found: C (63.22), H (4.84), N(12.37), S (6.91).

Example 37(d)6-[6-fluoro-2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 37(d) was prepared in a similar manner to that described forExample 37(a) except that methylamine was used instead of ethoxyamine:¹H NMR (300 MHz, dmso-d6) δ 8.37 (m, 1H), 8.18 (m, 1H), 7.87 (d, 1H),7.67 (d, 1H, J=16.4 Hz), 7.59 (dt, 1H), 7.40 (d, H), 7.30 (m, 2H), 7.20(m, 4H), 6.85 (d, 1H), 2.49 (d, 3H); LCMS (100% area) Rt=4.63 min, (pos)[M+H]/z Calc'd 405.1, found 405.2, (neg) [M−H]/z Calc'd 403.1, found403.1. Analyzed with 0.2 DMF, 0.3 CH₂Cl₂ (nmr), 0.3H₂O Calc'd, C(61.13), H (4.39), N (13.07), S (7.13). Found: C (61.08), H (4.35), N(13.14), S (7.22).

Example 38(a)6-[2-(2-Methylquinol-6-ylcarbamoyl)phenylsulfanyl]-3-E-(2-styryl)-1H-indazole

Example 38(a) was prepared in a similar manner to that described forExample 33(b) except that steps (i) and (ii) were omitted: ¹H NMR (300MHz, CDCl₃) δ 8.58 (s, 1H), 8.13 (s, 1H), 7.80 (m, 3H), 7.67 (t, 1H),7.43 (m, 2H), 7347.16 (m, 9H), 7.13 (d, 1H), 7.07 (d, 1H), 2.60 (s, 3H).LCMS (100% area) Rt=3.87 min, (pos) [M+H]/z Calc'd 513.1, found 513.2.

Example 38(b)6-[2-((4-piperizin-1-yl-3-trifluoromethylphenyl)carbamoyl)phenylsulfanyl]-3-E-(2-styryl)-1H-indazole

Example 38(b) was prepared in a similar manner to that described forExample 38(a) except that 3-trifluoromethyl-piperazin-1-yl-phenylaminewas used instead of 6-amino-2-methylquinoline: ¹H NMR (300 MHz, CDCl₃) δ8.75 (s, 1H), 7.95 (d, 1H), 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (m, 3H),7.40-7.25 (m, 9H), 7.20 (d, 1H), 3.00 (m, 4H), 2.83 (m, 4H). LCMS (100%area) Rt=3.94 min, (pos) [M+H]/z Calc'd 600.2, found 600.2. Analyzedwith 0.1 hex (nmr), 1.4H₂O Calc'd, C (63.71), H (5.12), N (11.06), S(5.06). Found: C (63.67), H (5.06), N (10.98), S (5.00).

Example 39(a)6-[2(Methylcarbamoyl)phenylamino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

A solution ofN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide(39 mg, 0.07820 mmol) (synthesis described below), ethylene diamine (21μL, 0.3128 mmol), and 1M TBAF in THF (0.63 ml, 0.6256 mmol), was stirredin a 90° C. oil bath for 2 hr. The crude reaction mixture was dilutedwith ethyl acetate (50 mL), extracted 1M sodium bicarbonate solution(2×20 ml), brine (5×20 ml), dried magnesium sulfate, filtered, andconcentrated to a solid. The solid was dissolved in THF, concentrated toan oil, then triturated with CH₂Cl₂/Et₂O, causing precipitation of apowder. The powder was collected by filtration, rinsed with Et₂O, anddried under high vacuum. Mass of collected solid was 20 mg (70% yield).¹H NMR (DMSO d6) δ 12.91 (bs, 1H), 9.86 (s, 1H), 8.60 (d, J=4.0 Hz, 1H),8.52 (m, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.80 (dt,J=1.7, 7.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H),7.47-7.34 (m, 2H), 7.25 (m, 2H), 7.00 (d, J=9.6 Hz, 1H), 6.89 (t, J=7.0Hz, 1H), 2.79 (d, J=4.7 Hz, 3H). Anal. Calcd. for C₂₂H₁₉N₅O.0.5 CH₂Cl₂:C. 65.61; H, 4.89; N. 17.00. Found: C, 65.52; H, 5.08; N, 16.78.The starting material was prepared as follows:

A solution of 191 mg (0.4 mmol) of6-iodo-3-carboxaldehyde-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole(from Example 33(a), step(ii)), methyl anthranilate (120.1 mg, 0.8mmol). 2-(dicyclohexylphosphino) biphenyl (28 mg, 0.08 mmol), Pd₂(dba)₃(18.4 mg, 0.02 mmol), K₃PO₄ (212.3 mg, 1.0 mmol), dissolved in dry DME(1.0 mL), was vacuum flushed with argon (3×), then stirred under anargon atmosphere for 3 d in an oil bath at 80° C. The crude mixture wasfiltered through a plug of SiO₂ eluted with ethyl acetate, then purifiedby “chromatotron” radial chromatography eluted with 25% CH₃CN/CH₂Cl₂.The mass of the fractions that were pure was 42 mg. An addition 120 mgof product that was ˜90% pure was also collected. The total yield ofN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl) 1-(2-trimethylsilanylethoxymethyl)-1H-indazol-6-ylamino)-benzamide was 162 mg or ˜81%.

Example 39(b)6-[2-(Prop-2-ynylcarbamoyl)phenylamino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 39(b) was prepared in a similar manner to that described forExample 39(a) except that the propargylamine was used instead ofmethylamine. ¹H NMR (CDCl₃) δ 9.50 (s, i), 8.64 (d, J=4.5 Hz, 1H), 7.98(d, J=8.9 Hz, 1H), 7.90 (d, J=16.4 Hz, 1H), 7.70 (dt, J=1.7, 7.5 Hz,1H), 7.57 (d, J=16.3 Hz, 1H), 7.52-7.43 (m, 3H), 7.34 (dt, J=1.5, 7.2Hz, 1H), 7.26 (m, 3H), 7.34 (ddd, J=1.0, 4.9, 7.5 Hz, 1H), 7.09 (dd,J=1.7, 9.0 Hz, 1H), 6.85 (dt, J=1.0, 7.0 Hz, 1H), 6.33 (bs, 1H), 4.24(dd, J=2.6, 5.3 Hz, 2H), 2.30 (t, J=5.5 Hz, 1H). Anal. Calcd. forC₂₄H₁₉N₅O.0.25 CH₂Cl₂: C, 70.24; H. 4.74; N. 16.89. Found: C, 70.72; H,4.96; N, 16.55.

Example 40(a)6-(3-Amino-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 40(a) was prepared in a similar manner to that described forExample 11. ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 8.62 (d, 1H,J=3.86 Hz), 8.34 (d, 1H, J=8.5 Hz), 8.01 (dl 1H, J=16.36 Hz), 7.87 (s,1H), 7.83 (td, 1H, J=7.69 Hz, J=1.81 Hz), 7.58-7.71 (m, 3H), 7.29 (qd,1H, J=7.39 Hz, J=0.98 Hz), 7.21 (t, 1H, 3=7.77), 7.00 (t, 1H, J=1.86Hz), 6.90 (dt, 1H, J=6.15 Hz, J=1.40 Hz), 6.86 (m, 1H). 5.40 (bs, 2H).MS (ESI+) [M+H]/z Calc'd 446, found 446. Calc'd: C, 74.10; H, 4.74; N,16.46. Found: C, 72.72; H, 4.87; N, 16.02.The starting material was prepared as follows:

To m-amino-phenyl boronic acid (8.22 g, 60 mmol) in dimethyformamide (60ml) at 23° C. under an atmosphere of argon was added triethylamine (10ml, 72 mmol) and 4 (dimethylamino)pyridine (0.366 g, 3 mmol). Theresulting solution was heated to 50° C. Carbonic acid 4-nitro-phenylester 2-trimethylsilanyl-ethyl ester (20.4 g, 72 mmol) was added in 5 by4 g portions over 18 hours. After 44 h carbonic acid 4-nitro-phenylester 2-trimethylsilanyl-ethyl ester (3.4 g, 12 mmol) was added followedby triethylamine (1.7 ml, 12 mmol). After 63 h the reaction mixture wasconcentrated to an oil. Purification by silica gel chromatographyeluting with 3-7 to 7-3 ethyl acetate-hexane gave (3-boronicacid-phenyl)carbamic acid 2-trimethylsilanyl-ethyl ester (8.12 g, 48%):R_(f) sm 0.067, p 0.33 (ethyl acetate-hexane 1:1); ¹H NMR (300 MHz,CD₃OD) δ 7.64 (s, 1H), 7.49 (d, 1H, J=8.94 Hz), 7.26 (m, 2H), 4.23 (t,2H, 3=8.28 Hz), 1.06 (t, 2H, J=8.21 Hz) 0.72 (s, 9H). MS (ES) [M+Na]/zCalc'd 304, found 304.

A mixture of6-iodo-3-((E2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(7.1 g, 14.8 mmol), (3-boronic acid-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (8.32 g, 29.6 mmol),dichlorobis(triphenylphosphine)-palladium(II) (312 mg, 0.44 mmol),potassium carbonate (6.13 g, 44.4 mmol) and triethylamine (2.1 ml, 14.8)in anisole (60 ml) was heated to 80° C. under an atmosphere of carbonmonoxide. After 24 h more triethylamine (2.1 ml, 14.8 mmol) was added.After 33 hrs the reaction was determined to be complete by TLC analysis(ethyl acetate-hexane 7-3). The reaction mixture was cooled to 23° C.,then diluted with saturated NaHCO₃ (aq) (40 ml) and ethyl acetate (300ml). The phases were separated and the aqueous was extracted with ethylacetate (2×100 mls). The pooled ethyl acetate was washed with brine (100ml) and dried over Na₂SO₄, filtered and concentrated. Purification bysilica gel chromatography gave(3-{1-[3-(2-Pyridin-2-yl-ethyl)-1)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-phenyl)-carbamicacid 2-trimethylsilanyl-ethyl ester as a yellow glass (7.22 g, 79%). ¹HNMR (300 MHz. CDCl₃) δ 8.65 (d, 1H, J=3.93 Hz), 8.10 (d, 1H, J=8.54 Hz),8.04 (s, 1H), 7.94 (d, 1H, J=16.33 Hz), 7.82 (s, 1H), 7.66-7.77 (m, 3H),7.61 (d, 1H, J=16.35 Hz), 7.40-7.51 (m, 3H), 7.19 (m, 1H), 7.00 (s, 1H),5.77 (s, 2H), 4.25 (t, 2H, J=6.93 Hz), 3.60 (t, 2H, J=8.10 Hz), 1.04 (t,2H, J=6.79 Hz), 1.00 (t, 2H, J=8.13 Hz), 0.04 (s, 9H), 0.0 (s, 9H). MS(ESI+) [M+H]/z Calc'd 615, found 615.

Example 40(b)6-(3-Amino-4-methyl-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 40(b) was prepared in a similar manner to that of Example 40(a)except that in step (i) 4-methyl-3-amino-phenyl boronic acid, preparedas described below, was used in place of m-aminophenyl boronic acid. ¹HNMR (DMSO-d₆) δ 13.6 (s, 1H), 8.62 (d, 1H, J=3.81 Hz), 8.33 (d, 1H,J=8.47 Hz), 8.01 (d, 1H, J=16.36 Hz), 7.85 (s, 1H), 7.82 (dd 1H, J=7.60Hz, J=1.80 Hz), 7.70 (d, 1H, J=7.81 Hz), 7.63 (d, 1H, J=16.36 Hz), 7.57(dd, 1H, J=8.47 Hz, J=1.2 Hz), 7.29 (m, 1H), 7.12 (d, 1H, J=7.82 Hz),7.09 (d, 1H, J=1.64 Hz), 6.90 (dd, 1H, J=7.59 Hz, J=1.65 Hz), 5.16 (bs,1H), 2.16 (s, 1H). MS (ESI+) [M+H]/z Calc'd 355, Anal. Calc'd: C, 74.56;H, 5.12; N, 15.81. Found; C, 73.86; H, 5.25; N, 15.34.The starting material was prepared as follows:

A mixture of 4-methyl-3-nitro-phenyl boronic acid (3.34 g, 18.45 mmol)and 10% Pd/C (334 mg) in MeOH (30 ml) was hydrogenated (1 atm) at 23° C.After 22 h the reaction mixture was filtered through celite andconcentrated to give 3-amino-4-methyl phenyl boronic acid (2.53 g, 91%).¹H NMR (300 MHz, DMSO-d₆) δ 7.21 (s, 1H), 7.08 (d, 1H, J=7.5 Hz), 6.92(d, 1H, J=7.46 Hz), 4.81 (bs, 2H), 2.09 (s, 3H). MS (ESI) [M+H]/z Calc'd152, found 152.

Example 40(c)6-(5-Amino-2,4-dimethyl-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 40(c) was prepared in a similar manner to that of Example 40(a)except that in step (i) 2,4-dimethyl-3-amino-phenyl boronic acid(prepared as described below) was used in place of m-amino-phenylboronic acid: ¹H NMR (DMSO-d₆) δ 8.62 (d, 1H, J=3.78 Hz), 8.32 (d, 1H,J=8.48 Hz), 7.99 (d, 1H, J=16.35 Hz), 7.83 (td, 1H, J=7.68 Hz, J=1.8Hz), 7.80 (s, 1H), 7.69 (d, 1H, J=7.80 Hz), 7.64 (dd, 1H, J=8.47 Hz,J=1.27 Hz), 7.62 (d, 1H, J=16.36 Hz), 7.29 (m, 1H), 6.94 (s, 1H), 6.64(s, 1H), 4.87 (bs, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI+) [M+H]/zCalc'd 369, found 369. Anal. Calc'd: C, 74.98; H, 5.47; N, 15.21. Found:C, 73.85; H, 5.56; N, 14.49.The starting material was prepared as follows:

2,4-Diemthylphenyl boronic acid was made in a similar manner as that ofExample 24(a), step (vii), except 2,4-dimethyl bromobenzene was used asstarting material. ¹H NMR (CD₃OD) δ 7.13 (d, 1H, J=7.43 Hz), 7.00 (s,1H), 6.97 (d, 1H. J=7.49 Hz), 2.28 (s, 3H), 2.28 (s, 3H). LCMS (ESI+)[M+H]/z Calc'd 151, found 151.

To fuming nitric acid (1 ml) cooled to −40° C. was added TFA (1 ml). Theresulting mixture was allowed to warm slightly to −35° C. and2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in oneportion. After 1 h, ice was added and the heterogenous mixture wasfiltered. The resulting solid was suspended in Et₂O and extracted with3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidifiedwith 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). Thepooled organics were washed with brine, dried with Na₂SO₄ decanted andconcentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg,47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196.

3-Amino-4,6-dimethylphenyl boronic acid was prepared in a similar asthat described for Example 40(b), step (i). ¹H NMR (CD₃OD)δ 6.83 (s,2H), 6.64 (s, 1H), 2.17 (s, 3H), 2.13 (s, 3H).

Example 41(a) 6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

To a solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (323 mg,2.1 mmol, 2.1 equiv.) in DMF (5 ml) at 23° C. under argon was addeddiisopropylethylamine (365 μl, 2.1 mmol, 2.1 equiv.), HATU (798 mg, 2.1mmol, 2.1 equiv.) and DMAP (cat.). To the resulting solution was added6-(3-Amino-benzoyl)-3-E-(2-pyridin-2-yl)ethenyl)-1H-indazol (Example40(a), 340 mg, 1 mmol, 1 equiv.). The reaction was followed by HPLCuntil all the starting analine was consumed ˜2 h (this gave a mixture ofmono and bis acylated compounds). The reaction mixture was quenched withsaturated NaHCO₃, then diluted with water and extracted withethylacetate. The pooled EtOAc was washed with water, brine, dried withNa₂SO₄, filtered and concentrated to an oil. The oil was dissolved inmethanol (10 ml), K₂CO₃ (290 mg, 2.1 mmol, 2.1 equiv.) was added and theresulting mixture was stirred at 23° C. until the bis-acylated compoundwas consumed (˜30 min.). The reaction mixture was concentrated to anoil, then partitioned between water and EtOAc. The organic phase waswashed with brine, dried with Na₂SO₄, filtered and concentrated.Purification by silica gel chromatography (1:1-8:2ethylacetate-dichloromethane) gave Example 41(a). ¹H NMR (300 MHz,DMSO-dd) 13.6 (s, 1H), 10.3 (s, 1H), 8.62 (d, 1H, J=3.88 Hz), 8.38 (d,1H, J=851 Hz), 8.20 (s, 1H), 8.12 (td, 1H, J=7.58 Hz, =1.78 Hz), 8.02(d, 1H, J=16.36 Hz), 7.93 (s, 1H), 7.83 (td, 1H, J=7.61 Hz, J=1.7 Hz),7.70 (d, 1H, J=7.78 Hz), 7.65 (d, 1H, J=16.23 Hz), 7.65-7.53 (m, 3H),7.30 (m, 1H), 4.43 (q, 2H, J=7.07 Hz), 2.21 (s, 3H), 1.31 (t, 3H, J=7.07Hz). MS (ESI+) [M+H]/z Calc'd 477, found 477. Anal. Calc'd: C, 70.57; H,5.08; N, 7.64. Found: C, 70.46; H, 5.11; N, 17.61.

Example 41(b)6-[3-(pyridin-4-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl(ethenyl]-1H-indazole

Example 41(b) was prepared in a similar manner to that described forExample 41 (a), except that isonicotinic acid was used instead of2-ethyl-5-methyl-2H-pyrazole-3 arboxylic acid. ¹H NMR (300 MHz, CD₃OD) δ8.74 (d, 2H, J=206.04 Hz), 8.56 (d, 1H, J=4.14 Hz), 8.27 (m, 2H), 8.05(dt, 1H, J=7.97 Hz, J=1.64 Hz), 8.02 (s, 1H), 7.95 (d, 1H, J=16.55 Hz),7.83-7.91 (m, 3H), 7.73 (m, 2H), 756-7.67 (m, 3H), 7.32 (m, 1H). MS(ESI+) [M+H]/z Calc'd 446, found 446. Anal. Calc'd: C, 72.80; H, 4.30;N, 15.72. Found: C, 7159; H, 4.43; N, 15.33.

Example 41(c)6-(3-crotonylamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(c) was prepared in a similar manner to that described forExample 41(a), except that crotonic acid was used instead of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₄) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J=3.81 Hz), 8.37 (d,1H, J=8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, J=16.34 Hz), 7.99 (d, 1H,J=7.88 Hz), 7.83 (td, 1H, J=7.67 Hz, 1=1.78 Hz), 7.70 (d, 1H, J=7.85Hz), 7.65 (d. 1H, J=16.40 Hz), 7.63 (dd, 1H, J=8.43 Hz, J=1.23 Hz),7.47-7.56 (m, 2H), 7.29 (qd. 1H, J=7.39 Hz, 1=0.99 Hz), 6.82 (m, 1H,J=6.9 Hz), 6.11 (dd, J=15.21 Hz, J=1.68 Hz), 1.87 (d, 3H, J=6.89 Hz). MS(ESI+) [M+H]/z Calc'd 409, found 409. Anal. Calc'd: C, 73.51; H, 4.94;N. 13.72. Found: C, 72.15; H. 4.97; N, 13.39.

Example 41(d)6-[3-(indol-4-yl-carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(d) was prepared in a similar manner to that described forExample 41 (a), except that 1H-Indole-4-carboxylic acid was used insteadof 2-ethyl-S-methyl-2H-pyrazole-3-carboxylic acid. LCMS (ESI+) [M+H]/zCalc'd 484, found 484.

Example 41(e)6-[3-((5-acetylthien-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(e) was prepared in a similar manner to that described forExample 10.6 (s, 1H), 8.63 (d, 1H, J=3.83 Hz), 8.39 (d, 1H, J=8.51 Hz),8.20 (s, 1H), 8.14 (dt, 1H, J=7.25 Hz, J=2.05 Hz), 8.07 (d, 1H, J=4.09Hz), 8.02 (d, 1H, J=16.42 Hz), 8.00 (d, 1H, J=4.01 Hz), 7.94 (s, 1H),7.83 (td, 1H, J=7.69 Hz, J=1.78 Hz), 7.59-7.65 (m, 5H), 7.30 (qd, 1H,J=7.40 Hz, J=0.96 Hz), 2.58 (s, 3H). MS (ESI+) [M+H]/z Calc'd 493, found493. Anal. Calc'd: C, 68.28; H, 4.09; N, 11.37; S, 6.51. Found: C,66.07; H, 4.34; N, 10.91; S, 6.14.

Example 41(f)6-[3-(3,5-difluorophenylacetamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(f) was prepared in a similar manner to that described forExample 41 (a), except that (3,5-difluoro-phenyl)-acetic acid was usedinstead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300MHz, DMSO d4) δ 13.6 (bs, 1H), 10.5 (s, 1H), 8.62 (d, 1H, J=4.02 Hz),8.36 (d, 1H, J=8.51 Hz), 8.05 (s, 1H), 8.01 (d, 1H, J=16.38 Hz), 7.93(d, 1H, J=7.88 Hz), 7.90 (s, 1H), 7.83 (td, 1H, J=7.61 Hz, 1=1.77 Hz),7.70 (d, 1H, 1=7.85 Hz), 7.64 (d, 1H, J=16.33 Hz), 7.61 (dd, 1H, J=8.45Hz, J=1.15 Hz), 7.48-7.57 (m, 2H), 7.15-7.31 (m, 5H), 3.77 (s, 2H). MS(ESI+) [M+H]/z Calc'd 495, found 495.

Example 41(g)6-[3-((5-methyl-1H-pyrazol-3-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(g) was prepared in a similar manner to that described forExample 41(a), except that 5-methyl-2H-pyrazole-3-carboxylic acid wasused in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR(300 MHz, DMSO-d₆) δ 13.6 (bs, 1H), 13.0 (bs, 1H), 10.3 (bs, 1H), 8.63(d, 1H, J=3.95 Hz), 8.37 (d, 1H, J=8.66 Hz), 8.36 (s, 1H), 8.16 (d, 1H,J=7.55 Hz), 8.02 (d, 1H, J=16.37 Hz), 7.93 (s, 1H), 7.83 (dt, 1H, J=7.61Hz, J=1.73 Hz), 7.70 (d, 1H, J=7.82 Hz), 7.65 (d, 1H, J=16.36 Hz), 7.65(dd, 1H, J=8.55 Hz, 1=1.12 Hz), 7.52 (m, 2H), 7.29 (m, 1H), 6.50 (s,1H), 2.29 (s, 3H). MS (ESI+) [M+H]/z Calc'd 449, found 449. Anal.Calc'd: C, 69.63; H. 4.49; N, 18.74. Found: C, 68.53; H, 4.95; N, 17.47.

Example 41(h)6-[3-((2-RS-trans-methylcyclopropyl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(h) was prepared in a similar manner to that described forExample 41(a), except that 2-Methyl-cyclopropanecarboxylic acid was usedin place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. R_(f) sm0.32, R_(f) p 0.42 (ethyl acetate-dichloromethane 8:2). ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, J=4.75 Hz, J=0.96Hz), 8.36 (d, 1H, J=8.47 Hz), 8.06 (t, 1H, J=1.67 Hz), 8.01 (d, 1H,J=16.37 Hz), 7.90 (m, 2H), 7.83 (td, 1H, J=7.68 Hz, J=1.79 Hz), 7.70 (d,1H. J=7.84 Hz), 7.64 (d, 1H, J=16.35 Hz), 7.61 (dd, 1H, J=8.47 Hz,J=1.32 Hz), 7.51 (t, 1H, J=7.69 Hz), 7.45 (dt, 1H, J=7.68 Hz, J=1.50Hz), 729 (dq, 1H, J=7.41 Hz, J=1.04 Hz), 151 (m, 1H), 1.23 (m, 1H), 1.09(d, 3H, J=5.93), 1.01 (m, TH), 0.65 (m, 1H). MS (ESI+) [M+H]/z Calc'd423, found 423. Anal. Calc'd: C, 73.92; H, 5.25; N, 13.26. Found: C,71.41; H, 5.56; N, 13.27.

Example 41(i)6-[3-((1,5-dimethyl-1H-pyrazol-3-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(i) was prepared in a similar manner to that described forExample 41(a), except that 1,5-dimethyl-1H-pyrazole-3-carboxylic acidwas used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹HNMR (300 MHz, DMSO-d₆) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J=3.87Hz), 837 (d, 1H, J=8.49 Hz), 8.34 (d, 1H, 1=1.63 Hz), 8.16 (td, 1H,J=7.43 Hz, J=1.96 Hz), 8.02 (d, 1H, J=16.35 Hz), 7.92 (s, 1H), 7.83 (dt,1H, J=7.68 Hz, 1=1.79 Hz), 7.70 (d, 1H, J=7.84 Hz), 7.65 (d, 1H, 1=16.35Hz), 7.65 (dd, 1H, J=8.52 Hz, J=1.2 Hz), 7.52 (m, 2H), 7.29 (m, 1H), 655(s, 1H), 3.83 (s, 3H), 2.30 (s, 3H). MS (ESI+) [M+H]/z Calc'd 463, found463. Anal. Calc'd: C, 70.12; H, 4.79; N, 18.17. Found: C, 69.59; H.4.88; N. 17.86.

Example 41(i)6-[3-((3-methylpyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl-1H-indazole

Example 41(j) was prepared in a similar manner to that described forExample 41(a), except that 3-methyl-isonicotinic acid was used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₄) δ 13.6 (s, 1H), 10.7 (s, 1H), 8.62 (dd, 1H, J=4.72 Hz, J=0.86Hz), 8.57 (s, 1H), 8.55 (d, 1H, J=4.91 Hz), 8.37 (d, 1H, J=8.46 Hz),8.20 (s, 1H), 8.07 (dt, 1H, J=7.27 Hz, J=1.99 Hz), 8.02 (d, 1H, J=16.37Hz), 7.93 (s, 1H), 7.83 (td, 1H, J=7.69 Hz, 1=1.79 Hz), 7.70 (d, 1H,J=7.84 Hz), 7.64 (d, 1H, J=16.27 Hz), 7.55-7.65 (m, 3H), 7.48 (d, 1H,J=4.89 Hz), 7.30 (qd, 1H, J=7.39 Hz, J=1.02 Hz), 2.38 (s, 3H). MS (ESI+)[M+H]/z Calc'd 460, found 460.

Example 41(k)6-[3-(cyclopropylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(k) was prepared in similar manner as Example 41(a) exceptthat cyclopropane carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃/MeOD) δ852 (d, 1H, J=3.9 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.93 (s, 1H), 7.85-7.80(m, 3H), 7.71-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.39 (1H, t, J=7.8 Hz),7.16 (1H, qd, J=6.3, 1.5 Hz), 1.62-1.57 (m, 1H), 125-1.84 (m, 2H),0.87-0.81 (m, 2H). HRMS (MALDI) C₂₅H₂₀N₄O₂ [M+H⁺]/z Calc'd 409.1659,found 409.1660.

Example 41(l)6-[3-((2-RS-trans-phenylcyclopropyl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(l) was prepared in similar manner as Example 41(a) exceptthat (1S,2S)-2-phenyl-cyclopropanecarboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃/MeOD) δ8.60 (d, 1H, J=4.2 Hz), 8.17 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.91 (t,3H, J=8.1 Hz), 7.78-7.71 (m, 2H), 7.63-7.56 (s, 3H), 7.47 (t, 1H),7.32-7.12 (m, 5H), 2.60-254 (n, 1H), 1.94-1.90 (m, 1H), 1.69 (q, 1H,J=4.8 Hz), 1.37-1.32 (m, 1H). HRMS C₃₁H₂₄N₄O₂ Calc'd (M+H⁺)/z 485.1993,found 485.1995.

Example 41(m)6-[3-((3-methylisoxazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(m) was prepared in similar manner as Example 41 (a) exceptthat 3-methyl-isoxazole-5-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.95(1H, s), 8.68 (1, d, J=4.2 Hz), 8.44 (d, 1H, J=8.7 Hz), 8.35 (s 1H),8.21-8.18 (m, 1H,), 8.08 (d, 1H, J=16.2 Hz), 7.98 (s, 1H), 7.87 (td, 1H,J=7.5, 1.8 Hz), 7.76-7.64 (m, 6H), 7.37-7.33 (m, 1H), 6.72 (s, 1H), 3.36(s, 3H). HRMS (MALDI) C₂₆H₁₉N₅O₃ [M+H⁺]/z: Calc'd 450.1561, found450.1570.

Example 41(n) 6-[3-((3-t-butyl-1-methyl-1H-pyrazol-5yl)carboxamide)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(n) was prepared in similar manner as Example 41 (a) exceptthat 5-tert-butyl-2-Methyl-2H-pyrazole-3-carboxylic acid used in placeof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃/MeOD) δ8.59 (d, 1H, J=4.8 Hz), 8.14 (d, 1H, J=8.4 Hz), 8.08-8.04 (m, 1H,),7.98-7.92 (m, 3H), 7.75 (td, 1H, J=7.8, 1.8 Hz), 7.68 (dd, 1H, J=8.4Hz), 7.61-7.56 (m, 3H), 7.52 (t, 1H, J=8.70 Hz), 7.25-7.21 (m, 1H,),6.75 (s, 1H,), 4.12 (s, 3H), 1.30 (s, 9H). HRMS (MALDI)C₃₀H₂₈N₆O₂[M+H⁺]/z: Calc. 505.2347, found 505.2353.

Example 41(o)6-[3-((5-chlorothien-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(o) was prepared in similar manner as Example 41(a) exceptthat 5-chlorothiophene-2-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 1058(s, 1H,), 8.68 (d, 1H, J=4.2 Hz), 8.43 (d, 1H, J=8.5 Hz), 8.22 (s, 1H,),8.15 (dt, 1H, J=7.5, 2.0 Hz), 8.08 (d, 1H, J=16.4 Hz), 8.007.98 (m, 3H),7.88 (td, 1H, J=7.7, 1.9 Hz), 7.78-7.62 (m, 4H,), 7.33 (d, 2H, J=4.1Hz). HRMS (MALDI) C₂₆H₁₇N₄O₂ClS [M+H⁺[/z: Calc. 485.0843, found485.0853.

Example 41(p)6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(p) was prepared in similar manner as Example 41(a) exceptthat 2,5-dimethyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3 carboxylic acid. HPLC: R_(t) 3.90 min(100% area). ¹H NMR (CDCl₃) δ 852 (d, 1H, J=4.8 Hz), 8.10 (d, 1H, J=8.4Hz), 7.98 (d, 1H, J=8.1 Hz), 7.93 (s, 1H,), 7.88-7.80 (m, 3H), 7.71-7.62(m, 2H), 756-7.49 (m, 4H), 7.44 (t, 1H, J=7.8 Hz), 7.16 (dd, 1H, J=7.1,4.8 Hz). HRMS (MALDI) C₂₇H₂₂N₆O₂.[M+H+]/z: Calc. 463.1877, found465.1889.

Example 41(q)6-[3-((2-chloro-6-methylpyridin-4-yl)carboxamido)benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(q) was prepared in similar manner as Example 41(a) exceptthat 2-chloro-6-methyl-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.11 min.(100% area). ¹H NMR (DMSO-d6) δ 10.77 (s, 1H), 8.68 (d, 1H, J=3.9 Hz),8.44 (d, 1H, J=8.4 Hz), 8.28 (s, 1H), 8.21 (dt, 1H, J=6.9, 2.1 Hz), 8.08(d, 1H, J=16.2 Hz), 7.98 (s, 1H), 7.92-7.64 (m, 9H), 7.35 (dd, 1H,J=6.6, 4.8 Hz), 2.61 (s, 3H).

Example 41(r)6-[3-((1-n-propyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(r) was prepared in similar manner as Example 41(a) exceptthat 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) & 10.29(s, 1H), 8.58 (d, 1H, J=3.9 Hz), 8.33 (d, 1H, J=8.4 Hz), 8.13 (s, 1H),8.10 (dt, 1H, =5.4, 2.1 Hz), 7.96 (d, 1H, J=16.5 Hz), 7.87 (s, 1H), 7.78(td, 1H, J=7.5, 1.5 Hz), 7.61-7.49 (m, 6H), 7.24 (dd, 1H, J=6.9, 1.8Hz), 4.32 (t, 1H, J=6.90 Hz), 1.69 (q, 2H, J=7.2 Hz), 0.77 (t, 3H, 75Hz). HRMS (MALDI) C₂₈H₂₀ClN₅O₂. [M+H⁺]/z: Calc. 491.2190, found491.2203.

Example 41(s)6-[3-(4-t-butylbenzamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(s) was prepared in similar manner as Example 41(a) exceptthat 4-tert-butyl-benzoic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R, 4.67 min. (100%area). ¹H NMR (DMSO-d₆) δ 10.45 (s, 1H), 8.44 (d, 1H, J=8.4 Hz), 8.32(s, 1H), 8.22 (d, 1H, J=7.5 Hz), 8.07 (d, 1H, J=16.5 Hz), 7.99-7.95 (m,3H), 7.88 (td, 1H, J=7.7, 1.5 Hz), 7.69-7.59 (m, 7H), 7.38 (dd, 1H.13.5, 5.1 Hz), 1.36 (s, 9H).

Example 41(t)6-[3((1-Allyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(t) was prepared in similar manner as Example 41(a) exceptthat 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R, 4.11 min. (100%area). ¹H NMR (DMSO) δ 10.46 (s, 1H), 8.74 (t, 1H, J=5.1 Hz), 8.48 (d,1H, J=8.4 Hz), 8.28 (s, 1H), 8.22 (t, 1H, J=5.4, 2.1 Hz), 8.15-8.01 (m,3H), 7.39 (td, 1H, J=7.8, 1.8 Hz), 7.82-7.63 (m, 6H) 7.39 (td, 1H,J=7.7, 1.5 Hz), 6.146.02 (m, 1H), 5.22-5.03 (m, 4H), 2.38 (s, 3H). HRMS(MALDI) C₂₉H₂₄N₆O₂ (M+H⁺)/z: Calc. 489.2034, found 489.2035.

Example 41(u)6-[3-((2-chloro-6-methoxypyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(u) was prepared in similar manner as Example 41(a) exceptthat 2-chloro-6-methoxy-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R_(t): 4.37 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.74 (s, 1H), 8.68 (d, 1H, J=3.6 Hz),8.44 (d, 1H, J=8.4 Hz), 8.28 (s, 1H), 8.20 (td, 1H, 1=6.6, 2.4 Hz), 8.07(d, 1H, 1=16.2 Hz), 7.98 (s, 1H), 7.89 (td, 1H, J=7.7, 1.8 Hz),7.77-7.62 (m, 6H), 7.38 (s, 1H), 7.35 (dd, 1H, 1=6.9, 1.8 Hz), 3.98 (s,3H).

Example 41(v)6-[3-((3-Ethyl-1-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(v) was prepared in similar manner as Example 41(a) exceptthat 5-ethyl-2-methyl-2H-pyrazole-3 carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. R_(t) 4.16 min. (100%area). ¹H NMR (DMSO-d₆) δ 10.44 (s, 1H), 8.73 (d, 1H, =3.0 Hz), 8.78 (d,1H, 8.7 Hz), 8.30 (s, 1H), 8.23 (d, 1H, J=6.9 Hz), 8.14-8.03 (m, 2H),7.93 (t, 1H, 6.9 Hz), 7.82-7.63 (m, 6H), 7.40 (t, 1H, J=6.3 Hz), 7.01(s, 1H), 4.12 (s, 1H), 2.68 (q, 21H, 7.8 Hz), 1.30 (t, 3H, J=7.5 Hz).HRMS (MALDI) C₂₈H₂₄N₆O₂ (M⁺]/z: Calc. 477.2034, found 477.2054.

Example 41(w)6-[3-((2-chloropyridin-4-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(w) was prepared in similar manner as Example 41(a) exceptthat 2-chloro-isonicotinic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R_(t): 3.99 min.(100% area). ¹H NMR (DMSO-d₆) δ 10.88 (s, 1H), 7.33 (d, 2H, H=4.8 Hz),8.49 (d, 1H, J=8.4 Hz), 8.33 (s, 12)), 8.26 (td, 1H, J=6.9, 3.0 Hz),8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H), 7.40 (t, 1H, =4.8 Hz).

Example 41(x)6-[3((1-Isopropyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(x) was prepared in similar manner as Example 41(a) exceptthat 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.19 min.(100% area). ¹H NMR (DMSO) δ 10.46 (s=1H), 8.72 (t, 1H, J=4.8 Hz), 8.48(s, 1H, J=d9.0 Hz), 8.31 (s. 3H), 8.21 (td, (H, 3=9.6, 2.1 Hz),8.15-7.98 (m, 2( ), 7.96-7.84 (m, 1H), 7.82-7.65 (m, 5H), 7.427.38 (m,1H), 6.88 (s, 1H), 5.645.38 (m, 1H), 2.32 (s, 3H), 1.48 (d, 1H, J=6.6Hz). HRMS (MALDI) C₁₉H₂₆N₆O₂ (M+H⁺]/z; Calc. 491.2190, found 491.2194.

Example 41(y)6-[3-(isopropoxycarbonylamino)benzoyl]-3-E-[pyridin-2-yl)ethenyl]-1H-indazole

Example 41(y) was prepared in similar manner as Example 41(a) exceptthat isopropyl chloroformate was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 9.97(s, 1H), 8.72 (t, 2H, J=4.8 Hz), 8.47 (d, 1H, J=8.7 Hz), 8.347.96 (m,3H), 8.01-7.87 (m, 2H), 7.82-7.69 (m, 2H), 7.52 (dt, 1H, J=7.5, 1.2 Hz),7.42-7.36 (m, 2H), 3.68 (d, 2H, J=6.6 Hz), 2.02 (m, 1H), 1.02 (d, 6H.J=6.6 Hz). HRMS (MALDI) C₂₆H₂₄N₄O₃ M+H⁺]/z: Calc' 441.1921, found441.1937.

Example 41(z)6-[3-((4-chloropyridin-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(z) was prepared in similar manner as Example 41(a) exceptthat used 4-chloro-pyridine-2 arboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R₁: 4.40 min. (100%area). ¹H NMR (DMSO-d₆) δ 10.99 (s, 1H), 8.72 (d, 1H, J=5.4 Hz), 8.63(d, 1H, J=3.9 Hz), 8.44 (s, 1H), 8.38 (d, 1H, J=8.4 Hz), 8.25 (dt, 1H,3=6.6, 2.4 Hz), 8.16 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=16.2 Hz), 7.94(s, 1H), 7.86-7.80 (m, 2H), 7.72-7.58 (m, 5H), 7.29 (dd, 1H, J=6.9, 6.0Hz).

Example 41(aa)6-[3-pyridin-2-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-imidazole

Example 41(aa) was prepared in a similar manner to that described forExample 41(a), except that pyridine-2-carboxylic acid was used insteadof 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMF-d₆) δ 10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, J=4.78 Hz, 0.94 Hz),8.46 (s, 1H), 8.38 (d, 1H. J 8.48 Hz), 8.25 (dt, 1H, J=7.17 Hz, 8=2.05Hz), 8.16 (dt, 1H, J=7.738 Hz, J=1.04 Hz), 8.07 (td, 1H, J=7.56 Hz,J=1.67 Hz), 8.02 (d, 1H, J=16.28 Hz), 7.95 (s, 1H), 7.83 (td, 1H, J=7.65Hz, 8=1.81 Hz), 7.22-7.66 (m, 47, 7.30 (qd, 1H, J=7.40 Hz, 3=1.02 Hz).MS (ESI+) [M+H]/z Calc'd 446, found 446.

Example 41(bb)6-[3-(3-methoxybenzamido)benzoyl]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazole

Example 41(bb) was prepared in similar manner as Example 41(a) exceptthat 3-methoxybenzoic acid used in place of2-ethyl-5-methyl-2H-pyrazole-3 carboxylic acid. ¹H NMR (DMSO-d₆) δ 10.50(s, 1H,), 8.67 (d, 1H, J=3.9 Hz), 8.46 (d, 1H, J=8.7 Hz), 8.33 (s, 1H),8.22 (dt, 1H, J=7.8, 1.8), 8.08 (d, 1H, J=15.0 Hz), 8.00 (s, 1H,),7.78-7.54 (m, 8H), 7.51 (t, 1H, 7.8 Hz), 7.38-7.33 (m, 1H), 7.23 (dd,1H, J=75, 1.5 Hz), 3.90 (s, 3H). HRMS (MALDI) C₂₉H₂₂N₄O₃. [M+H⁺]/z:Calc. 475.1765, found 475.1763.

Example 41(cc)6-[3-(phenoxyamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(cc) was prepared in a similar manner to that described forExample 41(a), except that phenyl chloroformate was used instead of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. mp 212-217° C., ¹H NMR(300 MHz, DMSO-d₆) δ 13.63 (s, 1H), 1051 (s, 1H), 8.62 (d, I, J=4.3 Hz),8.36 (d, 1H, J=8.6 Hz), 8.04-7.81 (m, 5H), 7.71-7.40 (m, 7H), 7.31-7.22(m, 4H). ESIMS m/z 461 [M+H]⁺. Anal. calc'd for C₂₈H₂₀N₄O₃×0.3 H₂O(465.9 g mol⁻¹): C, 72.18; H, 4.46; N, 11.33. Found: C, 72.41; H. 4.63;N, 11.57.

Example 41(dd)6-[3-(3,3-dimethylacrylamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(dd) was prepared in a similar manner to that described forExample 41 (a), except that 3,3-dimethylacrylic acid was used instead of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹H NMR (300 MHz,DMSO-d₆) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J=3.81 Hz), 8.37 (d,1H, J=8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, J=16.34 Hz), 7.99(d, 1H,J=7.88 Hz), 7.83 (td, 1H, J=7.67 Hz, 3=1.78 Hz), 7.70 (d, J H, =7.85Hz), 7.63 (dd, 1H, J=8143 Hz, J 71.23 Hz), 747-7.56 (m, 2H), 7.29 (qd,1H, J=7.39 Hz, J=0.99 Hz), 6.82 (m, 1H, J=6.9 Hz), 5.85 (s, 3H), 2.12(s, 3H), 1.85 (s, 3H). MS (ESI+) [M+H)/z Calc'd 409, found 409. Anal.Calc'd for C26H22N4O2×0.33 TBME: C, 7354; H, 5.80; N, 12.41. Found: C,73.26; H, 5.76; N, 12.36.

Example 41(ee)6-[3-(1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41 (e) was prepared in similar manner as Example 41 (a) exceptthat Example 40( ) was used in place of Example 40(a). ¹H NMR (DMSO-d₆)δ 13.6 (s, 1H), 9.94 (s, 1H), 8.62 (d, 1H, J=3.8 Hz), 8.36 (d, 1H,J=8.51 Hz), 8.01 (d, 1H, J=1636 Hz), 7.91 (s, 1H), 7.84 (dd, 1H, 3=7.66Hz, J=1.74 Hz), 7.81 (s, 1H), 7.70 (d, 1H, J=7.9 Hz), 7.64 (d, 1H,J=16.5 Hz), 7.62 (m, 2H), 7.50 (d, 1H, J=7.83 Hz), 7.29 (m, 1H), 6.82(s, 1H), 4.42 (qm 2H, J=7.06 Hz), 2.36 (s, 3H), 2.21 (s, 3H), 1.30 (t,3H, 1=87.09 Hz). MS (ESI+) [M+H]/z Calc'd 491, found 491. Anal. Calc'd:C, 71.00; H. 5.34; N, 17.13. Found: C, 70.80; H, 5.38; N, 17.00.

Example 41(ff)6-[3-((1-Allyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(ff) was prepared in a similar manner to that described forExample 41 (ee), except that 2-ally-5-methyl-2H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. ¹H NMR (DMSO-d₆) δ 13.6 (s, 1H), 9.98 (s, 1H), 8.62 (d, 1H, J=4.60Hz), 8.36 (d, 1H, J=8.46 Hz), 8.01 (d, 1H, J=16.37 Hz), 7.91 (s, 1H),7.83 (td, 1H, 3=7.69 Hz. 3=1.77 Hz), 7.78 (d, 1H, J=1.73), 7.70 (d. 1K,J=7.78 Hz), 759-7.70 (m, 3H), 7.50 (d, 1H, J=8.01 Hz), 7.29 (qd, 2H,J=7.46 Hz, 3=1.02 Hz), 6.86 (s, 1H), 5.95 (m, 1H), 4.93-5.10 (m, 4H),2.34 (s, 3H), 2.22 (s, 3H). LCMS (EI+) [M+H]/z Calc'd 503, found 503.Anal. Calc'd: C. 71.70; H. 5.21; N, 16.72. Found: C, 70.98; H, 5.42; N,15.94.

Example 41(gg)6-(3-acetamido-4-methylbenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(g) was prepared in a similar manner to that described forExample 41 (ee), except that acetyl chloride was used in place of2-ethyl-5-methyl-2H pyrazole-3-carboxylic acid. ¹H NMR (CD₃OD) δ 8.57(d, 1H, J=4.90 Hz), 8.13 (d, 1H, J=8.49 Hz), 7.99 (s, 1H), 7.95 (d, 1H,3=16.53 Hz), 7.89 (d, 1H, J=1.46 Hz), 7.86 (td, 1H, J=7.64 Hz, 1=1.73Hz), 7.73 (d, 1H, J=7.05 Hz), 7.62-7.69 (m, 2H), 7.65 (d, 1H, J=16.48Hz), 7.44 (d, 1H, J=7.97 Hz), 7.32 (qd, 1H, J=7.44 Hz. J=1.03 Hz), 2.38(s, 3H), 2.18 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 397, found 397. Anal.Calc'd: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.29; H, 5.09; N, 13.98.

Example 41(hh)6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(hh) was prepared in a similar manner to that described forExample 41 (ee), except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acidwas used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid.HPLC R_(t): 3.92 min., (100% area). ¹H NMR (DMSO) δ 10.02 (s, 1H), 8.74(d, 1H, J=3.6 Hz), 8.49 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=16.3 Hz), 8.03(s, 1H), 7.96-7.93 (m, 2H), 7.84-7.72 (m, 4H), 7.63 (d, 1H, 8.1 Hz),7.42 (dd, 1H, J=6.8, 1.5 Hz), 6.95 (s, 1H), 4.11 (s, 1H), 2.48 (s, 1H),2.32 (s, 1H).

Example 41(ii)6-[3-((1-n-propyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(ii) was prepared in a similar manner to that described forExample 41(ee), except that 5-methyl-2-propyl-2H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. HPLC: R, 4.16 min. (100% area). ¹H NMR (DMSO-d₆) δ 10.29 (s, 1H),8.58 (d, 1H, 3.9 Hz), 8.33 (d, 1H, J=8.4 Hz), 8.13 (s, 1H), 8.10 (dt,1H, J=5.4, 2.1 Hz), 7.96 (d, 1H, J=16.5 Hz), 7.87 (s, 1H), 7.78 (td, 1H,J=7.5, 1.5 Hz), 7.61-7.49 (m, 6H), 7.24 (dd, 1H, J=6.9, 1.8 Hz), 4.32(t, 2H, J=6.90 Hz), 2.58 (s, 3H), 2.22 (s, 3H) 1.69 (q, 2H, J=7.2 Hz),0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C₃₀H₂₆N₆O₂ [M+H⁺]/z: Calc. 505.2347,found 505.2343.

Example 41(jj)6-[3-((3-Ethyl-1-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(jj) was prepared in a similar manner to that described forExample 41(ee), except that 5-ethyl-2-methyl-2H-pyrazole-3-carboxylicacid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylicacid. ¹H NMR (DMSO-d₆) δ 10.78 (s, 1H), 9.43 (d, 1H, J=3.0 Hz), 9.15 (t,1H, J=9.6 Hz), 8.82 (dd, 1H, J=16.4, 1.5 Hz), 8.72-8.61 (m, 2H),8.52-8.30 (m, 4H), 8.10 (dd, 1H, J=6.9, 5.7), 7.93-7.89 (m, 1H),7.72-7.69 (m, 1H), 4.85 (s, 3H), 3.39 (q, 2H, J=7.8 Hz), 3.17 (s, 3H),2.10 (t, 3H, J=7.5 Hz). HRMS (MALDI) C₂₉H₂₆N₆O₂ (M+H⁺) m/z: Calc.491.2190, found 491.2211.

Example 41(kk)6-[3((1-Isopropyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-4-methylbenzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(kk) was prepared in a similar manner to that described forExample 41(ee), except that2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R_(t) 4.11 min.(100% area). ¹H NMR (DMSO-d₆) δ 9.99 (s, 1H), 8.68 (d, 1H, J=3.6 Hz),8.42 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, 3=16.4 Hz), 7.98 (s, 1H), 7.67-7.86(m, 2H), 7.77-7.65 (m, 4H), 7.56 (d, 1H, J=7.8 Hz), 7.37-7.33 (m, 1H),6.82 (s, 1H), 5.44-5.36 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 1.42 (d,6H, J=6.6 Hz). Anal. (C₃₀H₂₈N₆O₂.0.2H₂O) Calc'd: C, 5.63; N, 16.54.Found C, 7057; H, 5.70; N, 16.35.

Example 41(ll)6-[2,4-dimethyl-5-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(ll) was prepared in similar manner as Example 41(a) exceptthat Example 40(c) was used in place of Example 40(a). ¹H NMR (DMSO-d₆)δ 13.6 (s, 1H), 9.82 (s, 1H), 8.63 (d, 1H, J=3.84 Hz), 8.35 (d, 1H,J=8.54 Hz), 8.00 (d, 1H, J=16.37 Hz), 7.83 (s, 1H), 7.83 (td, 1H.,J=7.65 Hz, J=1.82 Hz), 7.69 (d, 1H, J=7.89 Hz), 7.65 (dd, 1H, J=8.52 Hz,J=1.36 Hz), 7.62 (d, 1H, J=16.34 Hz), 7.35 (s. 1H), 7.32 (s, 1H), 7.29(q d, 1H, J=7.42 Hz, 0.09 Hz), 6.78 (s, 1H), 4.39 (q, 2H, J=7.15 Hz),2.30 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.27 (t 3, 1H 7.15 Hz). LJMS(ESI+) [M+H]/z Calc'd 505, found 505.

Example 41(mm)6-[2,4-dimethyl-5-((1,3-dimethyl-1H-pyrazol-5-yl)-carboxamido)benzoyl]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazole

Example 41(mm) was prepared in a similar manner to that described forExample 41(ll), except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acidwas used in (S. 1H), 9.81 (S. 1H), 8.62 (d, 1H, 13.81 Hz), 8.35 (d, 1H,J=8.6 Hz), 8.00 (d, 1H, J=16.36 Hz), 7.83 (dt, 1H, J7.65 Hz, J=1.8 Hz),7.8 (s, 1H), 7.69 (d, 1H, J=7.88 Hz), 7.65 (dd, 1H, J=8.53 Hz, J=1.36Hz), 7.62 (d, 1H, J=16.35 Hz), 7.36 (s, 1H), 7.32 (s, 1H), 7.29 (qd, 1H,J=7.41 Hz, J=1.03 Hz), 6.79 (s, 1H), 3.96 (s, 3H), 2.30 (s, 3H), 2.25(s, 3H), 2.18 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 491, found 491. Anal.Calc'd: C. 71.00; H, 5.34; N, 17.13. Found: C, 70.69; H. 5.57; N, 16.26.

Example 41(nn)6-(5-acetamido-2,4-dimethylbenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 41(nn) was prepared in a similar manner to that described forExample 41(ll), except that acetyl chloride was used in place of2-ethyl-5-methyl-H-pyrazole-3-carboxylic acid. ¹H NMR (DMSO-d₆) δ 13.6(bs, 1H), 9.34 (s, 1H), 0.62 (d, 1H, 1=4.15 Hz), 8.33 (d, 1H, J=8.6 Hz),7.86 (d, 1H, J=16.36 Hz), 7.83 (td, 1H, J=7.71 Hz, J=1.82 Hz), 7.81 (s,1H), 7.69 (d, 1H, J=7.84 Hz), 7.64 (dd, 1H, J=1.38 Hz), 7.62 (d, 1H,J=16.46 Hz), 7.48 (s, H), 7.29 (qd, 1H, J=7.44 Hz, J=1.02 Hz), 7.24 (s,1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H). LCMS (ESI+) 1M+H]/zCalc'd 411, found 411.

Examples 41(oo)-41(lll) can be prepared in a similar manner to thatdescribed for Example 41(a).

Example 41(oo)

Example 41(pp)

Example 41(qq)

Example 41(rr)

Example 41(ss)

Example 41(tt)

Example 41(uu)

Example 41(vv)

Example 41(ww)

Example 41(xx)

Example 41(yy)

Example 41(zz)

Example 41(aaa)

Example 41(bbb)

Example 41(ccc)

Example 41(ddd)

Example 41(eee)

Example 41 (fff)

Example 41(ggg)

Example 41(hhh)

Example 41(iii)

Example 41(jjj)

Example 41(kkk)

Example 41(lll)

Example 42(a)6-(3-Benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl)-1H-indazole

Example 42(a) was prepared from6-(3-benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl-1H-indazolein a similar manner as that of Example 12. (0.58 g, 80.6%). HPLC 4.13min (98% area). ¹H NMR (CDCl₃) δ 8.66 (d, 1H, J=4.1 Hz), 8.24 (d, 1H,J=8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H), 7.83 (t, 2H, J=7.1 Hz),7.72-7.53 (m, 7H), 7.30 (qd, 1H, J=5.2, 1.1 Hz). HRMS (MALDI)C₂₈H₂₀N₄O₂. [M+H⁺]/z: Calc. 445.1664, found 445.1659. Anal.(C₂₆H₁₁N₅O₂.0.2EtOAc): C, 75.87; H, 4.78; N, 12.39.The starting material was prepared as follows:

To a stirred solution of 6-iodo-3-((E)-styryl)12-trimethylsilanyl-ethoxymethyl)1H-indazole (4.00 g, 8.40 mmol), fromExample 14 step (i), in anisole (48 mL) under an argon atmosphere wereadded bis(triphenylphosphine)palladium dichloride (176 mg, 0.25 mmol),TBACI (288 mg, 1.0 mmol), 2-butanol (1.54 mL, 16.8 mmol) and potassiumcarbonate (3.48 g, 25.2 mmol). The resulting mixture was stirred under acarbon monoxide atmosphere at 80° C. for 100 h. After removal of thesolvent by in vacuo concentration, the residue obtained was diluted withEtOAc (400 mL) and extracted with sat. NaCl (2×150 mL), sat. NaHCO₃(2×50 mL) and water (2×50 mL) then organic layer filter through 20 mL ofsilica. The organic filtrate was then concentrated in vacuo, to give anamber oil. Purification by flash chromatography with hexane:EtOAc (7:3)provided6-(3-aminobenzoyl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazoleas an amber oil upon concentration (2.38 g, 61% yield). ¹H NMR (CDCl₃) δ8.84 (dd, 1H, J=8.70, 0.90 Hz), 8.02 (s, 1H), 7.77 (dd, 1H, J=8.40, 1.0Hz), 7.62-7.59 (m, 2H), 7.40 (t, 2H, J=7.20 Hz), 7.38-7.24 (m, 4H),7.22-7.19 (m, 3H), 6.98 (dq, 1H, J=8.30, 0.90 Hz), 3.83 (brs, 2H,), 3.61(t, 2H, J=8.10 Hz), 0.91 (t, 2H, K=7.20 Hz), 0.17 (s, 9H).

To a stirred solution of6-(3-aminobenzoyl)-3-((E)-styryl)-112-trimethylsilanyl-ethoxymethyl)-1H-indazole(3.22 g, 6.87 mmol) in methylene chloride (10 mL) under an argonatmosphere was added benzoyl chloride (0.95 mL, 8.37 mmol) and pyridine(0.67 mL, 3.22 mmol). After 2 h the solution was diluted with 100 mL ofEtOAc and washed with saturated NaCl (1×50 mL), citric acid (1M, 2.5 pH,2×50 mL) and (50:50) NaHCO₃/water (2×50 mL). The organic layer was driedover Na₂SO₄ and filtered through 20 mL of silica The organic layer wasconcentrated in vacuo, to provide the product as a yellow solid.Purification using flash chromatography through silica eluting withhexane:EtOAc (7:3) afforded 6-(3-benzamidobenzoyl)-3-((E)styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole as a yellow foam(3.22 g, 85.1% yield). ¹H NMR (CDCl₃) δ 8.19 (d, 1H, J=8.7 Hz), 8.16 (s,1H,), 8.11-8.10 (m, 2H), 8.03-7.93 (m, 3H), 7.82(dd, 1H, J=8.4, 1.2 Hz),7.70-7.67 (m, 3H), 7.647.54 (m, 5H), 7.48 (t, 2H, J=14.1 Hz) 7.39 (1H,d, J=7.2 Hz).

A stirred solution of63-benzamidobenzoyl)-3-((E)-styryl)1-(2-trimethylsilanyl-ethoxy-methyl-1H-indazole(2.35 g, 4.07 mmol) in methylene chloride (45.6 mL) was cooled to −45°C. using acetonitrile/solid carbon dioxide bath. Ozone was then bubbledthrough the solution at a rate of 1.5 Lp)_(m), 60 amps for 15 minutes.The reaction mixture was quenched with the addition of hydrogen sulfide(2.5 mL) and warmed to 25° C. Removal of methylene chloride wasaccomplished by in vacuo concentration. The residue was purified throughsilica eluting with hexane:EtOAc (7:3) afforded 63benzamidobenzoyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazole-3-carboxaldehydeas an off-white foam (1.74 g, 85% yield). HPLC. 3.78 min (100% area); ¹HNMR (DMSO-d₆) δ 10.77 (s, 1H), 10.42 (s, 1H), 8.468.39 (m, 2H), 8.31(dt, 1H, J=6.0, 1.8 Hz), 8.19 (s, 1H,), 8.11-8.07 (m, 2H,), 7.91 (dd,1H, J=6.0, 1.2 Hz), 7.70-7.64 (m, 5H), 5.81 (s, 2H) 3.68 (t, 2H, J=6.9Hz), 0.98 (t, 2H, J=6.7 Hz), 0.02 (s, 9H).

To a stirred solution of 2-picolytriphenyphosphonium chloride w/sodiumhydride (2.23 g, 4.91 mmol) cooled to −78° C. was added6-(3-benzamidobenzoyl)-1-(2-trimethylsilanyl-thoxy-methyl)-1H-indazole-3-carboxaldehyde(1.26 g, 2.46 mmol) in 5 mL of THF anhydrous under an argon purge andstirred for 1 h at 0° C. and quenched via CH₃COOH/MeOH (1:1, mL). Thereaction mixture was diluted with 100 mL of EtOAc and partitionedbetween saturated NaCl (1×50 mL), and saturated NaHCO₃ (2×50 mL) thenthe organic layer dried over Na₂SO₄ and filter through 20 mL of silicaplug (3:1 trans/cis mixture). Purification with a 4 mm silica rotoreluting with hexane/EtOAc (1:1) afford63-benzamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleafter concentration as a yellow solid (1.05 g, 62%). ¹H NMR (CDCl₃) δ8.62 (d, 1H, 1=4.1 Hz), 8.22 (d, 1H, J=8.5 Hz), 8.11-8.10 (m, 3H),8.01-7.98 (m, 4H), 7.83 (t, 2H, J=7.1 Hz), 7.72-7.53 (m, 7H), 7.30 (qd,1H, J=5.2, 1.1 Hz), 5.81 (s, 2H) 3.68 (t, 2H, J=6.9 Hz), 0.98 (t, 2H,J=6.7 Hz), 0.02 (s, 9H).

Example 42(b)6-(3-Benzamidobenzoyl)-3-(1H-benzoimidazol-2-yl)-1H-indazole

Example 42(b) was prepared in a similar manner to that described forExample 42(a) except that step (iv) was replaced by the following. Tothe aldehyde prepared in Example 42(a), step (iii) was added1,2-diaminobenzene (0.011 g, 011 mmol), elemental sulfur (USP grade, 0.4g, 0.1201 mmol), 2 mL of anhydrous DMF and the mix was warmed to 90° C.for 18 h, cooled to 25° C. The reaction mixture was diluted with 10 mLof ethyl acetate and was washed with saturated NaCl (1×10 mL), NaHCO₃(1×10 Ml) and water 10 mL, dried over NaSO₄ and filter though a teflonfilter 0.22 μM and concentrated to a amber oil. Purification by radialchromatography followed by precipitation from 2 mL of methylene chlorideand hexane (2 mL) afforded intermediate as a white precipitated. ¹H NMR(Acetone-d6) δ 8.81 (d, 1H, J=8.6), 8.308.25 (m, 2H), 8.11 (s, 1H),8.02-7.99(m, 2H), 7.79 (td, 2H, J=12.2, 1.2 Hz), 7.63-7.47 (m, 7H),7.28-7.40 (m, 2H). HRMS (MALDI) m/z C₂₈H₁₉N₅O₂ Calc. (M+H⁺): 458.1617,found 458.1632.

Example 42(c)6-(3-Benzamidobenzoyl)-3-E-[2-(2-methylthiazol-4-yl)ethenyl]-1H-indazole

Example 42(c) was prepared in similar manner as 42(a) except4-(2-methylthiazyl)-methyltriphenylphosphonium chloride was used inplace of 2-picolytriphenyphosphonium chloride in step (iv). ¹H NMR(DMSO) δ 8.11-8.01 (m, 4H), 7.92 (d, 2H, J=6.9 Hz), 7.76-7.71 (m, 2H),7.65-7.62 (m, 1H), 7.567.48 (m, 5H,), 7.15 (s, 1H,), 2.81 (s, 3H). HRMS(MALDI) C₂₇H₂₀N₄O₂S (M+H⁺]/z: Calc. (M+H⁺) 465.1380, found 465.1373.

Example 42(d)6-(3-benzamidobenzoyl)-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1H-indazole

Example 42(d) was prepared in similar manner as 42(b) except1,2-diamine-2-pyridine was used in place of 1,2-diaminebenzene. HPLC:3.88 min (95% area); ¹H NMR (DMSO-d₆) δ 10.62 (s, 1H), 8.83 (d, 1H,J=8.4 Hz), 8.53 (s, 1H), 8.43 (s, 1H), 8.32 (dt, 1H, J=6.9, 1.8 Hz),8.15 (d, 1 h, J=12.9 Hz), 8.11-8.10 (m, 2H), 7.91 (d, 1H, J=9.0 Hz),7.72-7.65 (m, 6H), 7.43 (dd, 1H, J=6.3, 4.8 Hz). HRMS (MALDI) m/zC₂₇H₁₈N₆O₂ Calc. (M+H⁺): 459.1564, found 459.1558. Anal.(C₂₇H₁₈N₆O₂.0.4CH₂Cl₂): Calc. C, 66.83; H, 3.85; N, 17.07. Found: C,66.93; H. 4.04, N, 16.68.

Example 42(e)6-(3-benzamidobenzoyl)-3-E-[N-(4H-1,2,4-triazol-4-yl)iminomethyl]-1H-indazole

Example 42(e) was prepared in a similar manner as Example 42(a) exceptthat 4-amino 1,2,4 triazole and PPTS were used at 80° C. in place of2-picolytriphenyphosphonium chloride and potassium hydride at 23° C.HPLC R_(t): 4.05 min (96% area); ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H), 9.53(s, 1H), 9.40 (s, 2H), 8.56 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.26 (dt,1H, J=7.2, 2.1 Hz), 8.13 (s, 1H), 8.08-8.05 (m, 2H), 7.73-7.67 (m, 5H).HRMS (MALDI) C₂₄H₁₇N₇O₂ [M+H⁺]/z: Calc. 436.1516, found 436.1510. Anal.(C₂₄H₁₇N₇O₂.0.4hexane) Calc. C, 66.18; H, 4.67; N. 20.47. Found: C,65.78; H, 4.87, N, 20.47.

Example 436-(3-Benzamidobenzoyl)-3-E-[2-(2-formamidophenyl)ethenyl]-1H-indazole

Example 43 was prepared from6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazolein a similar manner to that described for Example 11. 18 mg (36%). HPLCR_(t): 4.19 min.

¹H NMR (CDCl₃) δ 8.43-7.92 (m, 6H), 7.68-7.49 (m, 4H) 7.39-7.36 (m, 3H),7.32-7.21 (m, 2H), 7.09-7.00 (m, 2H), 6.91-6.84 (m, 1H). HRMS (MALDI)C₃₀H₂₂N₄O₃ [M+Na]/z; Calc. 509.1590, found 509.1580. Anal.(C₃₀H₂₂N₄03*0.3H₂O) Calc'd: C, 73.25; H, 4.63; N, 11.39. Found: C,73.10; H, 4.58; N. 11.28.Starting material was prepared as follows:

6-(3-Benzamidobenzoyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indazole-3-carboxaldehyde(prepared in Example 42(a), step (iii)) was converted to6-(3-benzamidobenzoyl)-3-E-(2-nitrophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole in similar manner to that of Example 42(a), step (iv) exceptthat (2-nitrobenzyl)triphenylphosphonium bromide monohydrate was used inplace 2-picolytriphenyphosphonium chloride (0.19 g, 79%). ¹H NMR (CDCl₃)δ 8.15-7.93 (m, 5H), 7.89-7.86 (m, 3H), 7347.41 (m, 6H), 7.36-7.35 (m,2H), 7.21-7.18 (m, 2H), 7.036.91 (m, 1H), 3.643.46 (m. 2H), 0.96-0.79(m, 2H), −0.06(5, 91).

6-(3-Benzamidobenzoyl)-3-E-(2-nitrophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(0.19, 0.32 mmol) was dissolved in 3 mL of DMF, treated with SnCl₂ (0.26g, 1.40 mmol) and water (0.037 mL, 1.87 mmol), and was stirred for 3 hat 50° C. The reaction was quenched at 25° C. with 0.5 mL of 3N NaOH andthe precipitate was removed by filtration through celite. The solutionwas then partitioned between 50/50 saturated NaHCO₃/water (2×30 mL) andthe organic layer was filtered through a silica plug to give6-(3-benzamidobenzoyl)-3-E-(2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazoleas an amber oil (0.17 g, 92%). Product was used without furtherpurification.

6-(3-Benzamidobenzoyl)-3-E-(2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole(0.17, 0.28 mmol) was dissolved in 3 mL of methylene chloride. To thiswas added formic acid pentafluorophenyl ester (0.12 g, 0.56 mmol)dropwise. After 3 h, the reaction mixture was diluted with 40 mL ofEtOAc and was washed with 50/50 NaHCO₃ (2×30 mL) and the organic layerwas filtered through a silica plug. The residue was purified by radialchromatography through silica eluting with hexane:EtOAc/CH₂Cl₂ (1:1:1)which afforded6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazoleas a clear oil (63 mg, 40%). ¹H NMR (CDCl₃) δ 8.48-8.36 (m, 1H),8.207.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m,4H), 6.82 (t, 1H, J=14.2 Hz), 3.48-3.23 (m, 2H), 0.95-0.87 (m, 2H),−0.05 (s, 9H).

Example 446-(3-Aminobenzoyl)-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

Example 44 was prepared from the starting material described below in asimilar manner to that described for Example 12. R_(f) sm 0.6, p 0.5(ethyl acetate): ¹H NMR (300 MHz, CDCl₃) δ 8.8 (s, 1H), 85 (d, 1H), 7.95(s, 1H), 7.75 (d, 1H), 7.45-7.3 (m, 7H), 7.2 (m, 1H), 6.40 (s, 2H).The starting material was prepared as follows:

Aldehyde prepared in Example 33(a), step (i) (204 mg, 0.507 mmol) and1-aminopyrrole (67 μL, 0.66 mmol, 1.3 equiv) were stirred together intoluene (2 mL). To this mix was added PPTS (1 mg) and the solution washeated to 80° C. for 1 h. The mixture was cooled and was partitionedbetween 2:8 ethyl acetate-hexane and water. The organic material wasdried over sodium sulfate, decanted and concentrated under reducedpressure. The product was crystallized from dichloromethane (0.5 mL) andmethanol (2 mL) (215.7 mg, 91%): ¹H NMR (300 MHz, C₆D₆) δ 8.71 (s, 1H),8.25 (d, 1H, J=8.5 Hz), 8.08 (s, 1H), 7.75 (d₁H, J=8.5 Hz), 6.35 (s,2H), 5.85 (s, 2H).

A mixture of the above iodide (535 mg, 1.15 mmol, 1 equiv),3-aminophenyl boronic acid (236 mg, 1.72 mmol, 1.5 equiv), PdCl₂(PPh₃)₂(24 mg, 0.034 mg, 0.03 equiv), and potassium carbonate were taken up inanisole (6.7 mL) under carbon monoxide (1 atm). The mixture was heatedto 80° C. for 14 h. The mix was cooled, partitioned between ethylacetate and water. The organics were washed with saturated aqueoussodium bicarbonate, water and brine and the organic layer was separated.The organic material was dried over sodium sulfate, decanted andconcentrated under reduced pressure. Purification by silica gelchromatography (50 mL silica: 2:8 to 3:7 ethyl acetate-hexane) gaveproduct aniline as a solid (331 mg, 63%): R_(f) sm 0.60, p 0.21 (ethylacetate-hexane 3:7); ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.51 (d,1H, J=8.4 Hz), 8.06 (s, 1H), 7.76 (dd, 2H, 7=1.3, 8.4 Hz), 7.26 (m, 31),7.17 (m, 2H), 6.92 (m, 1H) 6.31 (t, 1H, J=2.3 Hz), 5.79 (s, 21), 3.84(s, 21), 3.60 (t, 2H, 3=8.2 Hz), 0.91 (t, 2H, 3=8.2 Hz), −0.08 (s, 9H).LCMS 4.98 min (pos) [M+H]/z Calc'd 460, found 460.

Example 45(a)6-[3-(Indol-4-ylcarboxamido)benzoyl]-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

Example 45(a) was prepared from Example 44 in a similar manner to thatdescribed for Example 12(d), except that indole-4-carboxylic acid wasused instead of 5-methyl-thiazole-2-carboxylic acid: R_(f) sm 0.0, p 0.2(ethyl acetate-benzene 1:3); ¹H NMR (300 MHz, dmso-d6) δ 9.84 (s, 1H),8.92 (s, 1H), 8.66 (s, 1H), 8.39 (d, 1H, 3=8.5 Hz), 8.02 (s, 1H), 7.86(m, 2H), 7.66 (d, 1H, 8=8.5 Hz), 7.52-7.40 (m, 4H), 7.27-7.07 (m, 5H),6.83 (s, 1H), 6.21 (s, 2H).

Example 45(a)6-(3-Benzamidobenzoyl)-3-E-[N-(pyrrol-1-yl)iminomethyl]-1H-indazole

Example 45(b) was prepared from Example 44 in a similar manner to thatdescribed for Example 12(d), except that benzoyl chloride was usedinstead of 5-methyl-thiazole-2-carboxylic acid and HATU: ¹H NMR (300MHz, CDCl₃) δ 11.9 (bs, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H,J=8.4 Hz), 7.99 (s, 1H), 7.9-7.8 (m, 4H), 7.65 (d, 1H, J=8.4 Hz), 7.48(t, 2H, J=7.8 Hz), 7.42-7.35 (m, 3H), 7.20 (t, 2H, 2.2 Hz), 6.28 (t, 2H,J=2.2 Hz).

Example 46 6-[N-(3-aminophenyl)amino]-3-E-styryl-1H-indazole

Example 46 was prepared from the starting material described below in asimilar manner to that described for Example 13(i). ¹H NMR (300 MHz,DMSO-d₆)° 12.6 (s, 1H), 8.07 (s, 1H), 7.97 (d, 1H, J=8.73 Hz), 7.69 (d,1H, J=8.49 Hz), 7.40 (m, 4H), 7.28 (m, 1H), 7.06 (d, 1H, J=1.49 Hz),6.44 (t, 1H, J=1.98 Hz), 6.34 (m, 1H), 6.14 (dd, 1H, J=7.88 Hz; J=1.26Hz), 5.01 (bs, 2H).

The compound prepared in Example 11, step (v), was converted to6-[N-(3-nitrophenyl)amino]-3-E-styryl-H-indazole in a similar manner tothat described for Example 12. ¹H NMR (300 z CDCl₃) δ 8.0 (m, 2H), 7.77(m, 1H), 7.64 (d, 2H, J=7.86 Hz), 7.41-7.56 (m, 6H), 7.3 (m, 2H), 7.08(d, 2H, J=8.67 Hz). MS (ESI+) [M+H]/z Calc'd 357, found 357. Calc'd: C,70.77; H, 4.53; N, 15.72. Found: C. 69.18; H, 4.51; N. 15.30.

Example 47 6-[N-(3-benzamido-4-fluorophenyl)amino]-3-E-styryl1H-indazole

6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl1H-indazolewas converted to Example 47 in a similar manner to that described forExample 11. ¹H NMR (300 MHz, DMSO-d₆) δ 12. (s, 1H, 10.0 (s, 1H), 8.38(bs, 1H), 8.02 (d, 1H, J=8.78), 7.98 (d, 2H, J=6.87 Hz), 7.69 (d, 2H,J=7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (t, 2H, J=7.28 Hz),7.53-7.30 (t, 2H, J=7.28 Hz), 7.53-7.30 m, 2H), &.07 (d, 1H, J=1.55 Hz),7.03 (m, 1H), 6.95 (dd, 1H), J=8.79 Hz, J=1.85 Hz), MS (ESI+) [M+H]/zCalc'd 449, found 449. Anal. Calc'd: C, 74.98. H, 4.72. N, 12.193 Found:C, 74.29. H, 4.76. N, 12.12.The starting material was prepared as follows:

To a solution of 2-fluoro-5-nitro-phenylamine (3.12 g, 20 mmol) indichloromethane (20 ml) at 23° C. under argon was added pyridine (1.94ml, 24 mmol) and benzoyl chloride (2.8 ml, 24 mmol). After 45 minutes awhite precipitate formed. The reaction mixture was concentrated in-vacuothen diluted with water and filtered to give a white solid which wasre-suspended in MeOH and filtered again givingN-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 93%). H NMR (300 MHz.CDCl₃) δ 9.48 (dd, 1H. 3=6.8 Hz, J=2.81 Hz), 8.17 (bs, 1H), 8.03 (m,1H), 7.92 (m, 2H), 7.52-7.65 (m, 3H), 7.31 (d, 1H, J=9.2 Hz).

A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g. 18.7 mmol)and 10% Pd/C (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) washydrogenated at 23° C. After 2.5 h the reaction mixture was filteredthrough celite and concentrated to giveN-(5-Amino-2-fluoro-phenyl)-benzamide (3.92 g, 91%). MS (ESI+) [M+H]/zCalc'd 231, found 231.

6-[N-(3-Benzamido-4-fluorophenyl)amino]-1-(2-trimethylsilanyl-ethoxymethyl-3-E-styryl1H-indazole was prepared in a similar manner as Example 48(a), step(iii) except that N-(5-amino-2-fluorophenyl)benzamide, and the compoundprepared in Example 14, step (i) were used as starting materials. ¹H NMR(300 MHz, CDCl₃) δ 8.38 (dd, 1H, J=6.84 Hz, J=2.73 Hz), 8.09 (d, 1H,J=3.08 Hz), 7.86-7.91 (m, 3H), 7.48-7.61 (m, 5H), 7.28-7.45 (m, 4H),7.19 (d, 1H, J=1.7 Hz), 7.08 (dd, 1H, J=10.48 Hz), 6.906.96 (n, 2H),6.03 (bs, 1H), 5.66 (s, 2H), 3.62 (t, 2H, J=8.14 Hz), 0.91 (t, 2H,J=8.32 Hz), 0.0 (s, 9H). MS (ESI+) [M+H]/z Calc'd 579, found 579. Anal.Calc'd: C, 70.56. H, 6.10. N. 9.68. Found: C, 20.26. H, 6.08. N, 9.16.

Example 48(a)6-[N-(5-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 48(a) was prepared in a similar manner as Example 41(a) from thestarting material described below. ¹H NMR (300 MHz, CD₃OD) δ 8.54 (d,1H, J=4.8 Hz), 7.95 (d, 1H, J=9.49 Hz), 7.84 (td, 1H, 1=7.71 Hz, =1.78Hz), 7.70 (d, 1H, J=7.95 Hz), 7.53 (d, 1H, J=16.59 Hz), 7.40 (d, 1H,J=7.92 Hz), 7.29 (qd, 1H, 1=7.45 Hz, J=1.07 Hz), 7.11 (d, 1H, 1=11.8),7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, J=7.16 Hz), 2.27 (s, 3H),2.26 (s, 3H), 1.38 (t, 3H, 1=7.11 Hz). MS (ESI+) [M+H]/z Calc'd 496,found 496. Anal. Calc'd: C, 67.86; H, 5.29; N, 19.79. Found: C, 66.24;H, 5.50; N, 18.61.The starting material was prepared as follows:

A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and10% Pd/C (200 mg) in MEOH (20 ml) was hydrogenated at 23° C. for 24 h.The reaction mixture was filtered through celite and concentrated.Purification by silica gel chromatography (1:1 ethyl acetate-hexane)gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%).

To a solution of carbonic acid 4-nitro-phenyl ester2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C.under an atmosphere of argon was added DMAP (12 mg. 0.1 mmol), DIEA(0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. Theresulting solution was heated to 50° C. for 48 h. The reaction mixturewas quenched with saturated NaHCO₃ (aq), extracted with EtOAc (3×20 ml).The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et₂Othen washed with 3 N NaOH (aq), water, brine, dried with Na₂SO₄,filtered and concentrated. Purification by silica gel chromatography(2:8-7:3 ethyl acetate-hexane) gave(5-amino-4-fluoro-2-methyl-phenyl)carbamic acid 2-trimethylsilanyl-ethylester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd 634, found 634.

To a mixture of 6-Iodo-3-((E)-2-pyridin-2-yl-vinyl)12-trimethylsilanyl-ethoxymethyl)1H-indazole (224 mg, 0.47 mmol),5-amino-4-fluoro-2-methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethylester (160 mg, 0.56 mmol), Cs₂CO₃ (214 mg, 0.66 mmol), PdCl₂(PPh₃)₂ (5.4mg, 0.0059 mmol) and BINAP (10 mg, 0.0176 mmol) under argon at 23° C.was added toluene (0.5 ml). The resulting mixture was heated to 80° C.for 16 h. The reaction mixture was cooled to 23° C. then diluted withwater (20 ml) and extracted with EtOAc (3×50 ml). The organics werewashed with water (30 ml), brine (30 ml), dried with Na₂SO₄ filtered andthe concentrated to a foam. Silica gel column (3:7 ethyl acetate-hexane)provided (4-Fluoro-2-methyl-5-[3(E)-2-pyridin-2-yl-vinyl)12-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-phenyl)carbamicacid 2-trimethylsilanyl-ethyl ester (98 mg, 33%). TLC (7-3 hexane-ethylacetate) Rfsm 0.42, Rfp 0.23. ¹H NMR (CDCl₃) δ 8.64 (dd, 1H, J=4.79 Hz,J=0.86 Hz), 7.94 (d, 1H, J=8.71 Hz), 7.91 (bs, 1H), 7.86 (d, 1H, J=16.41Hz), 7.69 (td, 1H, J=7.72 Hz, J=1.8 Hz), 7.55 (d, 1H, J=16.44 Hz), 7.49(d, 1H, J=7.91 Hz), 7.17 (qd, 1H. J=7.44 Hz, J=0.98 Hz), 6.99 (dd, 1H,J=8.67 Hz, J=1.89 Hz), 6.93 (d, 1H, J=11.2 Hz), 6.25 (bs, 1H), 5.95 (d,1H, J=1.97 Hz), 5.70 (s, 2H), 4.25 (t, 2H, J=8.53 Hz), 3.60 (t, 2H,J=8.24 Hz), 2.22 (s, 3H) 1.04 (t, 2H, J=8.54 Hz), 0.9 (t, 2H, J=8.25Hz), 0.05 (s, 9H), 0.0 (s, 9H). ¹³C NMR (CDCl₃, 75 MHz) δ 156.0, 154.4,149.8, 142.9, 142.8, 142.5, 136.6, 132.1, 130.1, 130.5, 128.7, 128.5,124.3, 122.2, 122.0, 121.8, 118.2, 117.3, 117.0, 115.1, 95.2, 77.6,77.4, 66.5, 63.7, 17.9, 17.2, −1.3. FTIR cm⁻¹: 3326, 2947, 1716, 1617,1534, 1514, 1244, 1057. MS (ESI+) [M+H]/z Calc'd 634, found 634.

The above aniline was prepared in a similar manner as Example 11. ¹H NMR(300 MHz, CD₃OD) δ 8.54 (m, 1H), 7.91 (dd, 1H, J=8.74 Hz, J=0.58 Hz),7.83 (td, 1H, J=7.72 Hz, J=1.79 Hz), 7.80 (d, 1H, 3=16.52 Hz), 7.69 (d,1H, J=7.98 Hz), 752 (d, 1H, J=1658 Hz), 7.29 (qd, 1H, J=7.43 Hz, J=1.07Hz), 6.94-6.99 (m, 2H), 6.83 (d, 1H, J=11.98 Hz), 6.82 (d, 1H, J=7.49Hz), 2.15 (s, 3H). MS (ESI+) [M+H]/z Calc'd 360, found 360.

Example 48(b)6-[N-(5-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 48(b) was prepared in a similar manner as Example 48(a) exceptthat 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used in place of2-ethyl-5-methyl-2H-pyrazole-3 carboxylic acid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.8 (s, 1H), 9.71 (s, 1H), 859 (m, 1H), 8.11 (s, 1H), 8.00(d, 1H, J=8.75 Hz), 7.87 (d, 1H, J=16.37 Hz), 7.80 (td, 1H, J=7.66 Hz,J=1.81 Hz), 7.64 (d, 1H, J=7.88 Hz), 7.49 (d, 1H, J=16.38 Hz), 7.34 (d,1H, J=8.16 Hz), 7.26 (m, 1H), 7.21 (d, 1H, J=12.14 Hz), 6.97 (dd, 1H,J=8.76 Hz), 6.88 (s, 1H), 6.79 (s, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 2.19(s, 3H). MS (ESI+) [M+H]/z Calc'd 482, found 482. Anal. Calc'd: C,67.35; H, 5.02; N, 20.36. Found: C, 66.83; H. 5.25; N, 19.68.

Example 49(a)6[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-4-fluoro-phenyl)amino]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazole

Example 49(a) was prepared in a similar manner as Example 48(a) exceptfor the following: 2,5-Dimethyl-2H-pyrazole-3 arboxylic acid was used inplace of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid; In step (iii),(5-Amino-2-fluoro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester,prepared as described below, was used instead of(5-amino-4-fluoro-2-methyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester, DME was the solvent andbiphenyl-2-yl-dicyclohexyl-phosphane was used as ligand. ¹H NMR (300MHz, CD₃OD) δ 12.7 (s, 1H), 9.94 (s, 1H), 8.48 (m, 1H), 8.40 (s, 1H),8.02 (d, 1H, J=6.77 Hz), 7.87 (d, 1H, J=16.37 Hz), 7.80 (d, 1H, J=7.63Hz, J=1.81 Hz), 7.64 (d, 1H, J=7.88 Hz), 7.49 (d, 1H, J=16.39 Hz), 7.42(dd, 1H, J=6.65 Hz, J=2.68 Hz), 7.24 (m, 2H), 7.06 (m, 2H), 6.96 (dd,1H, J=8.81 Hz, J=1.82 Hz), 6.85 (s, 1H), 4.0 (s, 3H), 2.20 (s, 3H). MS(ESI+) [M+H]/z Calc'd 468, found 468. Anal. Calc'd: C, 66.80; H, 4.74;N, 20.97. Found: C, 66.01; H, 4.72; N, 20.81.

To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g, 54 mmol)in THF (40 ml) at 23° C. under an atmosphere of argon was added2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture wasstirred for 11 hours then heated to 50° C. for 2 hours. The reactionmixture was allowed to cool to 23° C. quenched with saturated NaHCO₃(aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate waswashed with 1N HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), driedwith Na₂SO₄, filtered and concentrated to a yellow solid. Silica gelchromatography (2:8 ethyl acetate-hexane) provided(2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester(12.3 g, 77%). ¹H NMR (300 MHz, CDCl₃) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63Hz), 7.89 (m 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz),1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299,found 299.

A mixture of (2-Fluoro-5-nitro-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (3.00 g, 10 mmol) and 10% Pd/C (300 mg)in methanol (30 ml) was hydrogenated at 23° C. The resulting mixture wasstirred for 24 h. The reaction mixture was filtered through celite andconcentrated to give (5-Amino-2-fluoro-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (2.62 g, 97%). ¹H NMR (300 MHz, CDCl ₃) δ7.52 (m, 1H), 6.85 (dd, 1H, J=10.8 Hz, J=8.69 Hz), 6.73 (bs, 1H), 6.28(m, 1H), 4.27 (t, 2H, J=8.57 Hz), 3.0-4.4 (bs, 2H), 1.06 (t, 2H, J=8.58Hz), 0.07 (s, 9H).

Example 49(b)6-[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 49(b) was prepared in a similar manner to Example 49(a) exceptthat 1-methyl-2-isocyanato-4-nitro-benzene was used instead of1-Fluoro-2-isocyanato-4-nitrobenzene in step (i). ¹H NMR (300 MHz.CDCl₃) δ 8.59 (m, 1H), 8.35 (s, 1H), 8.00 (d, 1H, J=8.73 Hz), 7.87 (d,1H, J=16.38 Hz), 7.80 (td, 1H, J=7.66 Hz, J=1.85 Hz), 7.64 (d, 1H,J=7.85 Hz), 7.49 (d, 1H, J=16.35 Hz), 7.26 (m, 1H), 7.19 (m, 2H), 7.09(d, 1H, J=1.48 Hz), 7.02 (dd, 1H, J=8.17 Hz, J=2.24 Hz), 6.97 (dd, 1H,J=8.79 Hz, J=1.80 Hz), 6.81 (bs, 1H), 4.00 (s, 3H), 2.20 (s, 3H), 2.18(s, 3H). LCMS (ESI+) [M+H]/z Calc'd 464, found 464.

Example 49(c)6-[N-(3-acetamido-4-fluorophenyl)amino]-3-E-[2(pyridin-2-yl)ethenyl]-1H-indazole

Example 49(c) was prepared in a similar manner to Example 49(a) exceptthat acetic anhydride was used instead of 2,5-dimethyl-2H-pyrazole-3carboxylic acid: ¹H NMR (300 MHz, CD₃OD) δ 8.44 (m, 1H), 7.82 (d, 1H),7.70 (m, 3H), 7.55 (d, 1H), 7.41 (d, 1H, J=16.4 Hz), 7.19 (m, 1H), 7.03(s, 1H), 6.94 (m, 1H), 6.87 (m, 2H), 2.11 (s, 3H). LCMS (100% area)Rt=4.53 min, (pos) [M+H]/z Calc'd 388.4, found 388.4.

Examples 49(d)-49(x) can be prepared in a similar manner to thatdescribed for Example 49(a).

Example 49(d)

Example 49(e)

Example 49(f)

Example 49(g)

Example 49(h)

Example 49(i)

Example 49(j)

Example 49(k)

Example 49(l)

Example 49(m)

Example 49(n)

Example 49(O)

Example 49(p)

Example 49(q)

Example 49(r)

Example 49(s)

Example 49(t)

Example 49(u)

Example 49(v)

Example 49(w)

Example 49(x)

Example 506[3-(5-amino-2-fluorophenyl)carbamoyl-S-methyl-2-ethyl-2H-pyrazol-4-yl]-3-E-[2(pyridin-2-yl)ethenyl]-1H-indazole

Example 50 was prepared from the starting material described below in asimilar manner to that described for Example 11. MS (ESI+) [M+H]/zCalc'd 482, found 482. Calc'd: C, 67.35; H, 5.02; N, 20.36. Found: C,66.70; H, 5.09; N, 19.95.

2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-fluoro-5-nitro-phenyl)-amide was prepared in a similar manner asExample 47, step (i) except that2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid and HATU were usedinstead of benzoyl chloride. MS (ESI+) [M+H]/z Calc'd 293, found 293.

2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-fluoro-5-nitro-phenyl)-amide was prepared in a similar manner as40(b), step (i). MS (ESI+) [M+H]/z Calc'd 263, found 263.

6-[3-(5-amino-2-fluorophenyl)carbamoyl-5-methyl-2-ethyl-2H-pyrazol-4-yl]-3-E-[2-pyridin-2-yl)ethenyl]-12-trimethylsilanyl-ethoxymethyl)-1H-indazolewas prepared in a similar manner as Example 48(a), step (iii) except2-Ethyl-5-methyl-2H pyrazole-3-carboxylic acid(5-amino-2-fluoro-phenyl)-amide was used as starting material. MS (ESI+)[M+H]/z Calc'd 612, found 612.

Example 51 6-pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1H-indazole

6-Pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazolewas converted to6-pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)1H-indazole in a similarmanner to that described for Example 29(a). ¹H NMR (300 MHz, CDCl₃) δ8.76 (s, 1H), 8.67 (d, 2H, J=6.1 Hz), 8.53 (d, 1H, J=8.4 Hz), 7.74 (s,1H), 7.61 (d, 2H, J=6.2 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.27-7.25 (m, 2H),6.31-6.29 (m, 2H). MS (ES) [M+H]/z Calc'd 288, found 288. Anal. Calc'd,C (71.07), H (4.56), N (24.37). Found: C (70.81), H (4.57), N (24.14).The starting material was prepared as follows:

A solution of6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid(5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution wasthen evaporated under reduced pressure, and purified by silica gelchromatography to give6-pyrid-4-yl-3-E-(N-(pyrrol-1-yl)iminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole as an oil (140 mg, 57%). ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s,1H), 8.71 (d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=8.5 Hz), 8.34 (s, 1H), 7.85(d, 2H, J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=2.3 Hz), 6.25(t, 2H, J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz),0.86 (t, 2H, J=7.9 Hz), 0.00 (s, 9H).

Example 52(a) 6-(7-azaindazol-4-yl)-3-E-styryl-1H-indazole

Sem-Example 52(a) was converted to Example 52(a) in a similar manner tothat described for Example 27(a). ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d,1H, J=4.8 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.37 (s, 1H), 7.99 (s, 1H), 7.76(d, 2H, J=7.3 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.607.85 (m, 6H). HRMS (FAB)[M+H]/z Calc'd 338.1400, found 338.1389. Analyzed with 1.1trifluoroacetic acid, Calc'd, C (60.21). H (3.51), N (15.13). Found: C(59.93), H (3.59), N (14.86).The starting material was prepared as follows:

A solution of3-styryl-1-(2-triethylsilanyl-ethoxymethyl)-6-trimethylstanny]-1H-indazole(1.0 g, 1.90 mmol), 1-(4-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone(0.56 g, 1.90 mmol), AsPh₃ (116 mg, 0.38 mmol), and Pd₂ dba₃ (87 mg,0.09 mmol) in degassed dioxane (10 ml) was heated at 110° C. for 3 h.The solution was then diluted with ethyl acetate (50 ml), washed withbrine (2×10 ml), dried over MgSO₄, and concentrated under reducedpressure. Purification by silica gel chromatography gave Example 52(a)as a white solid (412 mg, 46%). ¹H NMR (300 MHz, CDCl₃) δ 8.82 (d, 1H,J=5.8 Hz), 8.52 (s, 1H), 8.29 (d, 1H, J=8.2 Hz), 8.05 (s, 1H), 7.73-7.32(m, 10H), 5.86 (s, 2H), 3.69 (t, 2H, J=8.2 Hz), 0.97 (t, 2H, J=8.2 Hz),0.03 (s, 9H).

A solution of6-iodo-3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g,6.10 mmol), hexamethylditin (2.00 g, 6.12 mmol), and Pd(Ph₃)₄ (282 mg,0.24 mmol) in degassed dioxane (10 ml) was heated at 110° C. for 3 h.The solution was then diluted with ethyl acetate (200 ml), washed withbrine (2×21 ml), dried over MgSO₄, and evaporated under reducedpressure. Purification by silica gel chromatography gave3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-6-trimethylstannyl-1H-indazoleas a yellow oil (3 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, 1H, J=7.4Hz), 7.71 (s, 1H), 7.71-7.29 (m, 8H), 5.77 (s, 2H), 3.65 (t, 2H, J=16.3Hz), 0.95 (t, 2H, J=16.4 Hz), 0.38 (s, 9H), −0.03 (s, 9H).

A mixture of 4-chloro-1H-pyrazolo[3,4-b]pyridine (820 mg, 5.30 mmol),sodium iodide (2.4 mg, 16.0 mmol), and acetyl chloride (0.8 ml) inacetonitrile (6 rid) was refluxed 8 h. The mixture was then treated witha 10% aqueous solution of NaCO₃ (10 ml), and a 10% aqueous solution ofNaHSO₃ (10 ml), and held 10 min. The mixture was extracted with ethylacetate (50 ml), and the organics were washed with brine (10 ml), driedover MgSO₄, and evaporated under reduced pressure. Purification bysilica gel chromatography gave 12-(5-iodo-pyrazolo[3,4-b]pyridin1-yl)ethanone as a brown solid (650 mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ8.39 (d, 1H, J=5.0 Hz), 8.04 (s, 1H), 7.76 (d, 1H, J=5.0 Hz), 2.88 (s,3H).

1,7-Dihydro-pyrazolo[3,4-b]pyridin-4-one (1.2 g, 8.8 mmol) (Dorn, H. etal., Prakt. Chem., 324, 557-62 (1982)) in POCl₃ (15 ml) at 0° C. wastreated with PCl₅ (2.5 mg, 0.01 mmol). The solution was allowed to warnto rt over 1 h, then heated to 90°c and held 3 h. The solution wasconcentrated under reduced pressure, then treated with ice and water (50ml). The resulting mixture was extracted with ethyl acetate (100 ml),and the organic layer was washed with a saturated aqueous solution ofsodium bicarbonate (30 ml). The organic layer was dried over MgSO₄, thenevaporated under reduced pressure to give4-chloro-1H-pyrazolo[3,4-b]pyridine as a yellow solid (820 mg, 60%). ¹HNMR (300 MHz, CDCl₃) δ 8.57 (d, 1H, J=52 Hz), 8.25 (s, 1H), 7.28 (d, 1H,J=5.2 Hz).

Example 52(b) 6-(7-azaindol-4-yl)-3-E-styryl-1H-indazole

Sem-iodoindazole was converted to Example 52(b) in a similar manner tothat described for Example 27(a). OH NMR (300 MHz, MeOH-d₄) δ 8.40 (d,1H, J=5.3 Hz), 8.53 (d, 1H, J=8.6 Hz), 7.74-7.35 (m, 10H), 6.90 (s, 1H).HRMS (FAB) [M+H]/z Calc'd 337.1448, found 337.1457. Analyzed with0.3H₂O, Calc'd, C (77.31), H (4.90), N (16.39). Found: C (77.51), H(4.88), N (16.27).The starting material was prepared as follows:

4-Chloro-1H-pyrrolo[2,3-b]pyridine (Clark, B. A. et al., J. Chem. Soc.P1, 2270-74 (1974)) was converted to 4-iodo-1H-pyrrolo[2,3-b]pyridine ina similar manner to that described for Example 52(a). 3H NMR (300 MHz,MeOH-d₄) δ 8.10 (m, 1H), 7.89 (d, 0.1H, J=5.0 Hz), 7.58 (m, 1H), 7.50(d, 1H, J=5.0 Hz), 6.26 (br s, 1H).

Example 53(a)3-(1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

To a solution of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(208 mg, 0.7 mmol) in dry dimethylformamide (6 mL) was added4-aminophenol (82 mg, 0.7 mmol) followed by HATU (312 mg, 0.8 mmol) andthen triethylamine (20 drops) was added. The reaction was stirredovernight at room temperature. LC/MS showed desired product as majorcomponent. The solvent was removed by vacuum. The residue remaining wastaken up in water and ethyl acetate. The layers were separated and theorganic layer was concentrated under vacuum. The residue was dissolvedin methanol (10 mL) and half of this solution was purified by HPLC usinga gradient of 5% acetonitrile/water to 55% acetonitrile/water over 60minutes with 0.1% trifluoroacetic acid in the water. The tide compoundwas isolated as a solid (20 mg). ¹H NMR (methanol-d₄) δ 6.87 (2H, d, 8.8Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d,8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1.The starting material was prepared as follows:

To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100 mL) wasadded NaNO₂ (856 g, 124.2 mmol). To this suspension was then slowlyadded dropwise via addition fuel 6N HCL (16 mL). The resulting slurrywas allowed to stir at room temperature overnight The solid precipitatewas filtered and washed with water (50 mL) to provide 2.35 g (100%) of3-formyl-1H-indazole-5-carboxylic acid. ¹H NMR (DMSO-d₆) δ 14.46 (1H,s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90 (1H, d,J=8.3 Hz). MS (APCI positive) 205 (methyl ester).

To 3-formyl-1H-indazole-6 carboxylic acid (2.35 g, 12.42 mmol) in DMF(60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfurpowder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for6 hours. The reaction was followed by TLC and LC-MS. After cooling,water (50 mL) was added to the reaction and the brown precipitate whichformed was filtered and collected to provide 3.1 g (90%) of3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. ¹H NMR(DMSO-d₆) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87(1H, d, l=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.

Example 53(b)3-(1H-Benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide

To 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (200 mg,0.719 mmol) in DMF (30 mL) was added cyclopropylamine (98 mg, 0.719mmol), HATU (0.719 mmol, 273 mg), and triethylamine (0.726 mmol, 0.1mL). This solution was allowed to stir at room temperature overnight Thereaction was worked up via aqueous wash and extraction with ethylacetate (3×50 mL). The organic layer was then dried with MgSO₄, filteredand concentrated to yield a dark oil. Flash column chromatography(30-70% Ethyl Acetate/Petroleum Ether) afforded the3-(1H-benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide as ayellow solid. (0.130 g, 57%) ¹H NMR (DMSO d) δ 13.88 (1H, s), 8.63 (1H,m), 8.51 (1H, d, J=8.5 Hz), 8.09 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.63(2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS(APCI positive) 318.1.

Example 53(c)3-(1H-benzoimidazol-2-yl)-N-(4-hydroxy-3-methylphenyl)-1H-indazole-6-carboxamide

Example 53(c) was prepared in a similar manner to that described forExample 53(a), except 3-methyl-4-aminophenol was used in place of4-aminophenol. ¹H NMR (DMSO-d₆) δ 8.59 (1H, d, J=8.3 Hz), 8.25 (1H, s),7.89 (1H, dd, J=1.3, 8.5 Hz), 7.68 (211, br s), 7.28 (2H, m), 7.14 (1H,d, J=8.5 Hz), 6.74 (1H, s), 6.68 (2H, dd, J=3.0, 8.3 Hz). MS (APCIpositive) 384.1.

Example 53(d)3-(1H-benzoimidazol-2-yl)-N-(4-hydroxy-2,3-dimethylphenyl)-1H-indazole-6-carboxamide

Example 53(d) was prepared in a similar manner to that described forExample 1553(a), except that 2,3-dimethylaminophenol was used in placeof 4-aminophenol. ¹H NMR (DMSO-d₆) δ 9.93 (1H, s), 9.22 (1H, s), 8.56(1H, d, J=8.5 Hz), 8.25 (1H, s), 7.90 (1H, d, J=8.5 Hz), 7.73 (1H, brs), 7.53 (1H, br s), 7.23 (2H, br s), 6.92 (1H, d, J=8.3 Hz), 6.68 (1H,d, J=8.5 Hz), 2.09 (6H, br s). MS (APCI positive) 398.4.

Example 53(e) 3-(1H-Benz imidaz 1-2-yl)-1H-indazole-6-carboxamide

Example 53(e) was prepared in a similar manner to that described forExample 53(a), except that 1,1,1,3,3,3-hexamethyldisilazane was used inplace of 4 aminophenol. ¹H NMR (DMSO-d₆) 13.91 (1H, s), 13.04 (1H, s),8.52 (1H, d, J=8.3 Hz), 8.20 (1H, br s), 8.15 (1H, s), 7.81 (1H, d.J=7.7 Hz), 7.75 (1H, d, J=6.6 Hz), 7.51 (2H, m), 7.21 (2H, m). MS (APCIpositive) 278.1.

Example 53(f)3-(1H-benzoimidazol-2-yl)-N-benzyloxy-1H-indazole-6-carboxamide

Example 53(f) was prepared in a similar manner to that described forExample 53(a) except that O-benzylhydroxylamine was used in place of4-aminophenol. ¹H NMR (DMSO-d₆) δ 13.94 (1H, s), 13.06 (1H, s), 11.97(1H, s), 8.55 (1H, d, J=8.8 Hz), 8.02 (1H, s), 7.78 (1H, d, J=8.3 Hz),7.52 (1H, d. J=8.3 Hz), 7.50 (3H, m), 7.40 (3H, m), 7.22 (2H, m), 4.97(2H, s). MS (APCI positive) 384.2.

Example 53(g) 3-(1H-benzoimidaz1-2-yl)-N-(3-fluoro-4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 53(g) was prepared in a similar manner to that described forExample 53(a) except that 3-fluoro-4-aminophenol was used in place of4-aminophenol. ¹H NMR (CH₃OD) δ 8.58 (1H, d, J=8.5 Hz), 8.20 (1H, s),7.84 (1H, d, J=8.7 Hz), 7.68 (2H, br s), 7.63 (1H, dd, J=2.4, 13 Hz),7.29 (3H, m), 6.92 (1H, t, J=9.2 Hz). MS (APCI positive) 388.3.

Example 54(a)3-(5,6-Difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Using the same procedure as for the synthesis of3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamideand 4,5-difluoro 1,2-phenylenediamine gave3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)1H-indazole-6-carboxamideas a tan solid. ¹H NMR (DMSO-d₆) δ 13.99 (1H, s), 13.27 (1H, s), 10.21(1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H,d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H,t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406.The starting material was prepared as follows:

To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4mmol) and 4 aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL,10.1 mmol). The reaction was stirred at room and monitored by TLC andLC/MS. After two hours the reaction was complete. The solvent wasremoved by vacuum and the product was purified by flash columnchromatography using ethyl acetate: petroleum ether 1:1 to pure ethylacetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide wasisolated as a tan colored solid. ¹H NMR (DMSO-d₆) δ 6.79 (2H, d, 8.9Hz), 759 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz),8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.

Example 54(b)3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(b) was prepared in a similar manner to that described forExample 54(a), except that 4,5-dichloro-1,2-phenylenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 14.08(1H, s), 13.38 (1H, s), 10.22 (1H, s), 9.27 (1H, s), 8.52 (1H, d, J=8.7Hz), 8.23 (1H, s), 8.02 (1H, s), 7.86 (1H, d, J=8.7 Hz), 7.70 (1H, s),7.55 (2H, d, J=8.7 Hz), 6.75 (2H, d. J=8.7 Hz). MS (APCI positive) 438.

Example 54(c)3-(5-Methoxy-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(c) was prepared in a similar manner to that described forExample 54(a), except that 4-methoxy-1,2-phenylenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 13.76(1H, s), 12.77 (1H, s), 10.13 (1H, s), 9.17 (1H, s), 8.45 (1H, d, J=8.3Hz), 8.11 (1H, s), 7.75 (1H, d, J=8.6 Hz), 7.46 (2H, d, J=8.7 Hz), 7.32(1H, d, J=8.3 Hz), 6.91 (1H, s), 6.77 (1H, m), 6.67 (2H, d, J=8.7 Hz),3.72 (3H, s). MS (APCI positive) 400.

Example 54(d)3-[1H-Naphtho(2,3-d)imidazol-2-yl]-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(d) was prepared in a similar manner to that described forExample 54(a), except that 2,3-naphthalenenediamine was used in place of4,5-difluoro 1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 14.11 (1H, s),13.10 (1H, s), 10.24 (1H, s), 9.27 (1H, s), 8.64 (1H, d, J=8.7 Hz), 8.28(1H, s), 8.25 (1H, s), 7.97 (2H, m), 7.73 (1H, br s), 7.89 (1H, d, 3=8.6Hz), 7.56 (2H, d, 3=8.7 Hz), 7.38 (2H, b), 6.76 (2H, d, J=8.7 Hz). MS(APCI positive) 420.

Example 54(e)3-[1H-Naphtho(1,2-d)imidazol-2-yl]-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(e) was prepared in a similar manner to that described forExample 54(a), except that 1,2-naphthalenenediamine was used in place of4,5-difluoro 1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 13.93 (1H, s),13.38 (1H, s), 10.23 (1H, s), 9.27 (1H, s), 8.70 (2H, m), 8.22 (1H, s),8.00 (1H, d, J=8.0 Hz), 7.87 (1H, m), 7.72 (3H, m), 7.57 (2H, d, J=8.7Hz), 6.76 (2H, d, J=8.6 Hz). MS (APCI positive) 420.

Example 54(f)3-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(f) was prepared in a similar manner to that described forExample 54(a), except that 3,4-dimethyl-1,2-phenylenediamine was used inplace of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (DMSO-d₆) δ 13.77(1H, d, tautomers), 12.70 (1H, d, tautomers), 10.11 (1H, s), 9.16 (1H,s), 8.48 (1H, d, J=8.3 Hz), 8.09 (1H, s), 7.73 (1H, d, J=8.6 Hz), 7.47(2H, d, J=8.7 Hz), 7.10 (1H, d, J=8.3 Hz), 6.93 (1H, d, J=8.3 Hz), 6.65(2H, d, J=8.7 Hz), 2.49 (3H, s), 2.24 (3H, s). MS, (APCI positive)398.4.

Example 54(g)3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazolecarboxamide

Example 54(g) was prepared in a similar manner to that described forExample 54(a), except that 4-tertbutyl-1,2-phenylenediamine was used inplace of 4,5-difluoro 1,2-phenylenediamine. ¹H NMR (acetone-d₆) δ 12.88(1H, s), 9.47 (1H, s), 8.63 (1H, d, J=8.7 Hz), 8.18 (1H, s), 7.82 (1H,d, 3=8.3 Hz), 757 (4H, m), 7.26 (1H, d. J=8.4 Hz), 6.74 (1H, d, J=8.3Hz), 1.31 (9H, s). MS (APCI positive) 426.

Example 54(h)3-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(h) was prepared in a similar manner to that described forExample 54(a), except that 4-trifluoromethyl-1,2-phenylenediamine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (methanol-di)δ 6.86 (2H, d, 8.9 Hz), 7.54 (2H, d, 8.9 Hz), 7.6 (1H, dd, 8.5 Hz), 7.83(1H, d. 8.3 Hz), 7.89 (1H, dd, 8.6 Hz), 8.04 (1H, br s), 8.25 (1H, s),8.61 (1H, d, 8.6 Hz). MS (APCI pos) 438.1.

Example 54(i)3-(5-Fluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(i) was prepared in a similar manner to that described forExample 54(a), except that 4-fluoro-1,2-phenylenediamine was used inplace of 4,5-difluoro 1.2-phenylenediamine. ¹H NMR (acetone-d₆) δ 13.40(1H, b), 12.47 (1H, b), 9.74 (1H, s), 8.67 (1H, d, J=8.6 Hz), 8.66 (1H,s), 8.29 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.67 (2H, J=8.4 Hz), 7.64 (1H,m), 7.40 (1H, m), 7.05 (1H, t, J=8.5 Hz), 6.83 (2H, d, J=8.4 Hz). MS(APCI pos) 388.

Example 54(j)3-(5H-[1,3]dioxolo[4,5-f]benzoimidazol-6-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(j) was prepared in a similar manner to that described forExample 54(a), except that 4,5-methylenedioxy-1,2-phenylenediamine wasused in place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (methanol-d₄)δ 6.85 (2H, d, 8.9 Hz), 7.15 (2H, s), 7.54 (2H, dl 8.9 Hz), 7.86 (1H,dd, 8.6 Hz), 8.23 (1H, s), 8.55 (1H, dd, 8.5 Hz). MS (APCI pos) 414.1.

Example 54(k)3-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(k) was prepared in a similar manner to that described forExample 54(a), except that 4,5-dimethoxy-1,2-phenylenediamine was usedin place of 4,5-difluoro-1,2-phenylenediamine. ¹H NMR (methanol-d₄) δ3.98 (6H, s), 6.85 (2H, d, 8.78 Hz), 7.29 (2H, br s), 7.54 (2H, d, 8.73Hz), 7.86 (1H, d, 857 Hz), 8.24 (1H, s), 8.57 (1H, d, 858 Hz). MS (APCIpos) 430.1.

Example 54(l)3-(5-Chloro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)-1H-indazole-6-carboxamide

Example 54(l) was prepared in a similar manner to that described forExample 54(a), except that 4-chloro-1,2-phenylenediamine was used inplace of 4,5-difluoro 1,2-phenylenediamine. ¹H NMR (methanol-d₄) δ 8.62(1H, d, J=8.6 Hz), 8.30 (1H, s), 7.90 (1H, dd, J₁=8.6 Hz, J2=1.3 Hz),7.69 (b, 2H), 7.56 (2H, d, J=6.89 Hz), 7.33 (1H, dd, J₁=8.59, J2=1.97Hz), 6.88 (2H, d, J=6.89 Hz). MS (APCI pos) 404.1.

Example 55 3-1H-Benzoimidazol-2-yl-6-pyridin-4-yl-1H-indazole

Sem-Example 55 was converted to Example 55 in a similar manner to thatdescribed for Example 27(a). ¹H NMR (300 MHz, CDCl₃+MeOH-d₄+DMSO-d₆) δ8.71-8.64 (m, 3H), 8.03 (s, 1H), 7.86 (dd, 2H, J=4.7.1.6 Hz), 7.77-7.72(m, 3H), 7.32 (dd, 2H, J=6.0, 3.1 Hz). HRMS (]AB) [M+H]/z Calc'd312.1244, found 312.1253. Analyzed with 1.40H₂O, Calc'd, C (67.80), H(4.73), N (20.81). Found: C (68.06), H (4.45), N (20.68).The starting material was prepared as follows:

A solution of6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde(0.70 g, 2.0 mmol), benzene-1,2-diamine (0.26 g, 2.4 mmol) and sulfur(77 mg, 2.4 mmol) in DMF (10 ml) was heated in an oil bath at 90° C.overnight. The resulting mixture was poured into brine (200 ml), thenextracted with EtOAc (3×60 ml). The combined organic layer was driedover MgSO₄ and concentrated under reduced pressure. The resulting oilwas purified by silica gel chromatography to yield6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazoleas a light brown oil (0.75 g, 65%). ¹H NMR (CDCl₃) δ 8.82 (d, 1H, J=8.5Hz), 8.73 (d, 1H, J=5.8 Hz), 7.947.89 (m, 2H), 7.87 (s, 1H), 7.69-7.62(m, 4H), 7.407.34 (m, 2H), 3.703.49 (m, 4H), 0.94 (t, 2H, J=8.3 Hz),0.67 (t, 2H, J=8.2 Hz), −0.03 (s, 9H), −0.13 (s, 9H).

Example 566-[3-(Propyn-3-ylcarbamoyl)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

A solution of2-{1-[3((E)-2-yl-2-vinyl)-1H-indazol-6-yl]-methanoyl}-benzoic acid (55.4mg. 0.15 mmol) (synthesis described below), propargyl amine (15.4 μL.0.225 mmol), and triethyl amine (41.8 μL 0.30 mmol), dissolved in DMF(1.5 hexafluorophosphate (62.7 mg, 0.165 mmol). After stirring for onehour the mixture was concentrated under high vacuum and purified bypreparative C18 reverse phase column chromatography. The resulting 40 mgof product was further purified by “chromatotron” radial chromatographyeluted with 25% CH₃CN/CH₂Cl₂, giving 16.5 mg of the product as a whitesolid (27% yield). ¹H NMR (DMSO-d₄) δ 13.30 (s, 1H), 8.58 (d, J=5.00 Hz,1H), 8.05 (d, J=8.29 Hz, 1H), 7.92 (d, J=16.2 Hz, 1H), 7.79. (m, 3H),7.63 (d, J=8.25 Hz, 1H) 7.53 (m, 3H), 7.32 (s, 1H), 7.27 (m, 2H), 6.89(d, J=8.48 Hz, 1H). Anal. Calcd. for C₂₅H₁N₄020.5H₂O: C, 72.27; H, 4.61;N, 13.49. Found: C, 72.39; H, 4.62; N, 13.69.

Synthesis of2-{1-[3-(E)-2-Pyridin-2-yl-vinyl)-1H-indazol-6-yl]-methanoyl}-benzoicacid. A solution of2-{1-[3-((E)-2-Pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-benzoicacid (402 mg, 0.805 mmol) (synthesis described below), ethylene diamine(215 μL, 3.22 mmol), and 1M TBAF in THF (6.44 ml, 6.44 mmol), wasstirred in a 90° C. oil bath for 4 hr. The crude reaction mixture wasquenched with acetic acid (386 μL, 6.44 mmol), diluted with ethylacetate (100 mL), extracted 1M sodium bicarbonate solution (2×20 ml),brine (5×20 ml), dried magnesium sulfate, filtered, and concentrated toa 3 mL volume. The resulting crude material was purified by preparativeC18 reverse phase column chromatography, giving 211 mg of the tidecompound as a yellow solid (71% yield). ¹H NMR (DMSO-d₆) δ 13.50 (bs,1H), 8.68 (d, J=5.27 Hz, 1H), 8.29 (d, J=8.86 Hz, 1H), 8.13-7.90 (m,4H), 7.81-7.43 (m, 7H).

Synthesis of2-{1-[3-((E)-2-Pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-benzoicacid. A solution 6-iodoindazole (477 mg, 1.0 mmol) dissolved in THF (10mL), at −100° C. was treated dropwise with 2.5 M n-butyl lithium inhexanes (440 μl, 1.10 mmol), stirred for 5 minutes at this temperature,then treated with a solution pthalic anhydride (222 mg, 1.5 mmol) in THF(1.0 mL). The resulting mixture was allowed to slowly warm to roomtemperature, where it was stripped of THF, diluted with ethyl acetate,extracted with 1 N citric acid, extracted with brine, dried overmagnesium sulfate, and concentrated to an oil. The oil was trituratedwith methylene chloride, and diethyl ether, giving 484 mg (81% yield) ofthe tide compound as a white solid. ¹H NMR (DMSO-d₆) δ 8.67 (d, J=5.09Hz, 1H), 8.31 (d, J=8.85 Hz, 1H), 8.08-7.55 (m, 4H), 750-737 (m, 2H),5.81 (s, 2H), 3.53 (t, J=8.10 Hz, 2H), 0.78 (t, J=8.15 Hz, 2H), 40.12(s, 9H).

Example 576-[3-((1,3-dimethyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole

Example 57 was prepared in a similar manner to that of Example 58. ¹HNMR (300 MHz, DMSO-d₆) δ 13.15 (s, 1H), 10.17 (s, 1H), 8.60 (d, 1H,J=4.2 Hz), 8.22 (d, 1H, J=8.7 Hz), 7.94 (d, 1H, J=16.4 Hz), 7.847.79 (m,1H), 7.68-7.50 (m, 4H), 7.40 (t, 1H, J=8.1 Hz), 7.30-7.26 (m, 1H), 7.06(s, 1H), 7.00 (dd, 1H, J=8.8, 1.9 Hz), 6.87 (dd, 1H, J=8.0, 1.9 Hz),6.79 (s, 1H), 3.96 (s, 3H), 2.17 (s, 3H); ESIMS m/z 451 [M+H]⁺. Anal.calcd for C₂₆H₂₂N₆O₂ ×0.5H₂O×0.4 hexanes (494.0 g/mol): C, 69.05; H.5.84; N, 17.01. Found: C, 68.78; H, 5.55; N, 17.05.

Example 586-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(1H-imidazol-2-yl)ethenyl]-1H-indazole

A solution of tetrabutylammonium fluoride (7.5 mL, 1.0 M in THF, 7.5mmol, 15.0 eq) and 1,2-diaminoethane (0.33 mL, 5.0 mmol, 10 eq) wasadded to 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[2-methyl-5-(1-(2-trimethylsilanyl-ethoxymethyl)-3-{(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)-phenyl]-amide(360 mg, 0.5 mmol, 1.0 eq) in 1,4-dioxane (5 mL) and the reactionmixture was heated to 90° C. for 18 hours. At the end of this time thereaction was concentrated under reduced pressure and the resultantorange oil was diluted with ethyl acetate (50 mL). The organic layer wasvigorously washed with saturated sodium bicarbonate (5×50 mL), brine,dried over magnesium sulfate and concentrated under reduced pressure togive a yellow solid (287 mg). The crude product was purified by radialchromatography on silica gel using 5% methanol-chloroform with 0.1%ammonium hydroxide (R_(f)0.1) as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(5-{3-[(E)-2-(1H-imidazol-2-yl)vinyl]-1H-indazol-6-yloxy}-2-methyl-phenyl)-amide(140 mg, 61%) as a light yellow solid: HPLC R_(t)=11.8 min.; TLCR_(f)=0.8 (10% methanol-chloroform with 0.1% ammonium hydroxide); ¹H NMR(300 MHz, DMSO-d₆) δ 13.03 (s, 1H), 12.30 (br. s, 1H), 9.78 (s, 1H),8.00 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, J=16.8 Hz), 7.32 (d, 1H, J=8.5 Hz),7.27 (d, 1H, J=16.9 Hz), 7.13-7.12 (m, 3H), 7.00-6.94 (m, 3H), 6.78 (s,1H), 4.39 (q, 2H, J=7.1 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.28 (t, 3H,J=7.1 Hz). Anal. calcd for C₂₆H₂N₇2×0.5H₂O×0.4 hexanes (511.0 g/mol): C,66.75; H, 6.23; N, 19.19. Found: C, 66.95; H, 6.25; N, 18.83.

The starting materials were prepared as follows:

(i) Preparation of 1-(2-trimethylsilanyl-ethoxymethyl)1H-imidazole

1H-Imidazole (2.0 g, 29.4 mmol, 1.0 eq) in THF (70 mL) was added to a 0°C. suspension of sodium hydride (1.5 g, 60% in mineral oil, 38.2 mmol,1.3 eq) in TH (30 mL). After gas evolution ceased, the mixture waswarmed to room temperature for 45 minutes and then recooled to 0° C.[2(Trimethylsilyl)ethoxy]methyl chloride (S. 4 mL, 30.2 mmol, 1.0 eq)was added, and the mixture was warmed to room temperature overnight. Thereaction was quenched with saturated sodium bicarbonate, the THF removedunder reduced pressure, and the resultant beige slurry extracted withethyl acetate. The extracts were combined, washed with brine, dried overmagnesium sulfate, filtered, and concentrated to give 6.9 g of an amberoil. The oil was purified by flash chromatography on silica gel using 2%methanol-chloroform as the eluant to give1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole as a light amber oil(4.7 g, 81%): TLC R_(f)=0.3 (5% methanol-chloroform); ¹H NMR (300 MHz,DMSO-d₆) δ 7.77 (s, 1H), 726 (d, 1H, J=1.2 Hz), 6.93 (s, 1H), 5.32 (s,2H), 3.45 (t, 2H, J=8.0 Hz), 0.83 (t, 2H, J=8.0 Hz), 0.05 (s, 9H); ³CNMR (75 MHz, DMSO-d₆) δ 137.9, 128.8, 119.6, 74.8, 65.1, 17.1, −1.4.(ii) Preparation of[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol

1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole (3.0 g, 15.4 mmol, 1.0eq) was dissolved in THF (150 mL) and cooled to −78° C. n-BuLi (10.6 mL,1.6 M in hexanes, 16.9 mmol, 1.1 eq) was added and the temperature wasallowed to increase to −40° C. over 15 minutes. The light yellowsolution was stirred for an additional 30 minutes at −40° C. then theanion was quenched with DMF (1.3 mL, 16.9 mmol, 1.1 eq). The reactionmixture was warmed to room temperature overnight then quenched withwater. The solvent was removed and the mixture was extracted withdichloromethane. The organic layer was washed with water, dried withbrine and magnesium sulfate, filtered and concentrated to give the crudeproduct (3.5 g; TLC R_(f)=0.5 (5% methanol-chloroform). The proton NMRspectrum gives the aldehyde proton at 9.73 ppm (300 MHz, DMSO-d₆). Thecrude product was dissolved in methanol (15 mL), cooled to 0° C., andtreated with sodium borohydride (1.2 g, 30.8 mmol, 2.0 eq). The reactionmixture was warmed to room temperature overnight. The solvent wasremoved and the crude product was diluted with chloroform, washed withwater, dried with brine and magnesium sulfate, filtered and concentratedto give a clear oil (3.6 g). The oil was purified by flashchromatography on silica gel using 3-6% methanol-chloroform with 0.1%ammonium hydroxide as the eluant to give[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as awhite solid (1.4 g, 41% 2-steps); TLC R_(f)=0.4 (8%methanol-chloroform); ¹H NMR (300 MHz, DMSO-d₆)δ 7.22(d, 1H, J=1.1 Hz),6.81 (d, 1H, J=1.0 Hz), 5.36 (s, 2H), 5.31 (br, t, 1H, J=5.2 Hz), 4.50(d, 2H, J=4.8 Hz), 3.48 (t, 2H, J=8.0 Hz), 0.83 (t, 2H, J=8.0 Hz), −0.05(s, 9H); ¹³C NMR (75 MHz, DMSO-d₆) δ 148.9, 127.8, 122.5, 75.5, 66.5,56.9, 18.5, 0.0.(iii) Preparation of2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazolehydrochloride

A solution of thionyl chloride (0.87 mL, 12.0 mmol, 3.0 eq) inchloroform (8 mL) was cooled to 0° C. and treated with a solution of[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (0.92 g,4.0 mmol, 1.0 eq) in chloroform (2 mL). The clear solution was stirredat 0° C. for 30 minutes and then at room temperature for 2 hours. Thesolvent was removed and the product was sequentially slurried andconcentrated using chloroform, toluene and cyclohexane to give2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)1H-imidazolehydrochloride as a beige solid (1.1 g, 97%): ¹H NMR (300 MHz, DMSO-d₆) δ7.85 (d, 1H, J=1.9 Hz), 7.70 (d, 1H, J=1.9 Hz), 5.62 (s, 2H), 5.14 (s,2H), 3.57 (t, 2H, J=8.3 Hz), 0.90 (t, 2H, J=8.3 Hz), −0.02 (s, 9H); ¹³CNMR (75 MHz, DMSO-d₆) δ 142.1, 123.2, 120.2, 76.5, 66.8, 31.7, 17.3,−1.4.(iv) Preparation of 3-amino-4-methyl-phenol

Black solid (95%); HPLC R_(t)=4.4 min.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.61(s, 1H), 6.64 (d, 1H, J=8.1 Hz), 6.05 (d, 1H, J=2.4 Hz), 5.88 (dd, 1H,J=8.0, 2.4 Hz), 4.64 (br. s. 2H), 1.92 (s, 3H); ¹³C NMR (75 MHz, DMSO) δ156.1, 147.2, 130.2, 111.7.103.3, 101.1, 16.6.(v) Preparation of 3-(benzhydrylidene-amino)methyl-phenol

Yellow solid (49%); mp 106-108° C.; HPLC R_(f)=153 min.; TLC R=0.2(10%ethyl acetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s, 1H),7.67-756 (m, 2H), 7.53-7.43 (m, 3H), 7.35-7.31 (m, 3H), 7.137.10 (m,2H), 6.82 (d, 1H, J=8.3 Hz), 6.22 (dd, 1H, J=8.1, 2.5 Hz), 5.88 (d, 1H,J=2.5 Hz), 1.97 (s, 3H); ¹³C NMR (75 MHz, DMSO-d) δ 166.4, 155.2, 150.6,138.9, 136.0, 130.8, 130.2, 128.7, 128.4, 128.2, 128.0, 117.3, 109.9,106.2, 17.0.(vi) Preparation ofbenzhydrylidene-{2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl}-amine

A round bottom flask was charged with potassium phosphate (5.5 g, 26.0mmol, 2.0 eq), 3-(benzhydrylidene-amino)-4-methyl-phenol (3.9 g, 13.6mmol 1.1 eq),6-iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazole(6.2 g, 13.0 mmol, 1.0 eq) and o-xylene (130 mL). The resultant slurrywas degassed, purged with argon and treated with a mixture oftris(dibenzylideneacetone)dipalladium(0) (916 mg, 1.1 mmol, 8 mol %) andbiphenyl-2-yl-di-tert-butyl-phosphane (656 mg, 2.2 mmol, 16 mol %). Theflask was immersed in an oil bath and stiffed at 100° C. for 18 hours.The black slurry was cooled to room temperature, filtered through celiteand concentrated. The black oil was dissolved in chloroform, washed withwater, brine, dried over magnesium sulfate, filtered and concentrated togive a black oil (12.1 g). The crude product was purified by flashchromatography on silica gel using 10-15% ether-cyclohexane as theeluant to give benzhydrylidene-[2-methyl-5-[3-((E)-styryl)(2-trimethylsilanyl-ethoxymethyl)1H-indazol-6-yloxy]-phenyl)-amine as ayellow foam from ether (1.4 g, 16%): HPLC R_(t)=24.3 min.; TLC R_(f)=0.5(20% ether-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, 1H, J=8.8Hz), 7.75-7.66 (m, 4H), 7.53-7.31 (m, 1H), 7.147.08 (m, 4H), 6.62 (dd,1H, J=8.8, 2.0 Hz), 6.55 (dd, 1H, J=8.2, 2.5 Hz), 6.20 (d. 1H, 1=2.4Hz), 5.64 (s, 2H), 3.51 (t, 2H, J=7.8 Hz), 2.12 (s, 3H), 0.78 (t, 2H,J=7.7 Hz), −0.14 (s, 9H).(vii) Preparation of2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenylamine

Amber oil (80%); HPLC R_(f)=21.0 min.; TLC R_(f)=0.4 (20% ethylacetate-cyclohexane); ¹H NMR (300 MHz, DMSO-4) δ 8.18 (d, 1H, J=8.8 Hz),7.747.71 (m, 2H), 752 (s, 2H), 7.43-7.38 (m, 2H), 7.33-7.28 (m, 1H),7.20 (d, 1H, J=2.0 Hz), 6.97-6.90 (m, 2H), 6.33 (d, 1H, J=2.4 Hz), 6.16(dd, 1H, J=8.0, 2.5 Hz), 5.66 (s, 2H), 5.01 (br. s, 2H), 3.52 (t, 2H,J=8.0 Hz), 2.03 (s, 3H), 0.80 (t, 2H, J=8.0 Hz), −0.11 (s, 9H).(viii) Preparation of 2-ethyl-5-methyl-2N-pyrazole-3-carboxylic acid(2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazol-6-yloxy]-phenyl}-amide

White foam (85%); HPLC R_(f)=21.5 min.; TLC R_(f) 0.2 (20% ethylacetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.24 (d,1H, J=8.8 Hz), 7.747.72 (m, 2H), 7.53 (s, 2H), 7.43-7.38 (m, 2H),7.347.28 (m, 3H), 7.12 (d, 1H, J=2.6 Hz), 7.00 (dd, 1H, J=8.8, 2.0 Hz),6.92 (dd, 1H, J=8.3, 2.5 Hz), 6.78 (s, 1H), 5.69 (s, 2H), 4.40 (q, 2H,J=7.1 Hz), 3.53 (t, 2H, J=7.9 Hz), 2.22 (s, 3H), 2.19 (s, 3H), 1.27 (t,3H, J=7.1 Hz), 0.78 (t, 2H, J=7.9 Hz), −0.15 (s, 9H).(ix) Preparation of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[5-[3-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-2-methyl-phenyl]-amide

A solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid{2-methyl-5-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yloxy]-phenyl}-amide(774 mg, 1.28 mmol, 1.0 eq) in 1,4-dioxane (8 mL) and water (2 mL) wastreated with osmium tetraoxide (7 mg, 0.03 mmol, 0.02 eq). The solutionwas stirred for 5 minutes then treated with sodium periodate (822 mg,3.84 mmol, 3.0 eq). The resultant thick tan slurry was stirred at roomtemperature overnight, poured into 15% Na₂S₂O₃ (100 mL) and extractedwith ethyl acetate. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to give an amber oil (902 mg). The crude product waspurified by radial chromatography on silica gel using 10-50% ethylacetate-clohexane as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid(5-[3-formyl-1-(2-trimethylsilanyl-ethoxymethyl-1H-indazol-6-yloxy]-2-methyl-phenyl)-amideas a beige solid from ether (590 mg, 86%): HPLC R_(t)=18.9 min.; TLCR_(f)=0.2 (40% ethyl acetate-cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ10.16 (s, 1H), 9.75 (s, 1H), 8.14 (d, 1H, J=8.8 Hz), 7.48 (d, 1H, J=1.8Hz), 7.32 (d, 1H, J=85 Hz), 7.16-7.13 (m, 2H), 6.93 (dd, 1H, J=8.3, 2.6Hz), 6.78 (s, 1H), 5.84(s, 2H), 4.39 (q, 2H, J=7.1 Hz), 355 (t, 2H,J=7.8 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J=7.2 Hz), 0.79 (t,2H, J=7.8 Hz), p. 15 (s, 9H).(x) Preparation of 2-ethyl-5-methyl-2H-pyrazole-3 arboxylic acid[2-methyl-5-(1-(2-trimethylsilanyl-ethoxymethyl)-3-{(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)-phenyl]-amide

A solution of2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazolehydrochloride (344 mg, 1.22 mmol, 2.0 eq) in chloroform (20 TEL) wasfree based with saturated sodium bicarbonate. The organic layer wasdried with brine and magnesium sulfate, filtered and concentrated togive an amber oil (301 mg, 100%). The resultant oil was dissolved inacetonitrile (12 mL), treated with triphenylphosphine (304 mg, 1.16mmol, 1.9 eq) and warmed to 70° C. for 18 hours. The solvent was removedand the crude12-trimethylsilanyl-ethoxymethyl)-2-[(triphenyl-λ⁵-phosphanyl)-methyl]-1H-imidazolechloride was dissolved in THF (12 mL), cooled to −78° C., and treatedwith potassium tert-butoxide (1.2 mL, 1.0 M in THF, 1.22 mmol, 2.0 eq).After 15 minutes, 2-ethyl-5-methyl-2-pyrazole-3-carboxylic acid{5-[3-formyl-1-(2-trimethylsilanyl-ethoxymethyl)1H-indazol-6-yloxy]-2-methyl-phenyl}-amide (325 mg, 0.61 mmol, 1.0 eq)in THF (1 mL) was added to the ylide at −78° C. The clear yellowsolution was warmed to room temperature overnight, quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated to givethe crude product as an amber oil (1.0 g). The crude product waspurified further by radial chromatography on silica gel using 0-5%methanol-chloroform as the eluant to give2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid[2-methyl-5-(12-trimethylsilanyl-ethoxymethyl)-3-{(E)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-vinyl}-1H-indazol-6-yloxy)phenyl]-amide as a tan solid upon standing overnight (390 mg, 88%). HPLCR_(t)=20.6 min.; TLC R_(f)=0.4 (4% methanol-dichloromethane); ¹H NMR(300 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.14 (d, 1H, J=8.8 Hz), 7.64 (d, 1H,J=16.2 Hz), 7.42 (d, 1H, J=16.3 Hz), 7.39-7.35 (m, 3H), 7.30 (d, 1H,J=85 Hz), 7.12 (d, 1H, J=2.5 Hz), 7.03 (s, 1H), 6.99 (dd, 1H, J=8.8, 1.9Hz), 6.78 (s, 1H), 5.70 (s, 2H), 5.55 (s, 2H), 4.40 (q, 2H, J=7.1 Hz),3.55-3.48 (m, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J=7.1 Hz),0.84 (t, 2H, J=7.9 Hz), 0.77 (t, 2H, J=7.9 Hz), −0.11 (s, 9H), −0.15 (s.9H).

Example 59(a)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

Example 41(a) (4.57 g, 9.59 mmol, 1 equiv) was taken up in methanol (96mL) and was protected from light with aluminum foil. A second flask withmethanol (20 mL) was treated with acetyl chloride (684 μL, 1.00 equiv)for 5 min. The acid solution was then added to the first mixture withseveral methanol washes (−20 mL). The volatile material was removedunder reduced pressure and the residue was triturated with 1:1 ethylacetate-hexane to give, after filtering and drying, a yellow powder(4.82 g, 98%): Analyzed with 1.0H₂O Calc'd, C (61.85), H (5.07), N(15.46). Found: C (61.15), H (5.15), N (15.38).

Example 59(b)6-[3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

Example 59(b) was prepared in similar manner as Example 59(a) exceptthat Example 41(p) was used in place of Example 41(a). HPLC: 3.92 min(100% area); ¹H NMR (DMSO) δ 10.45 (s, 1H), 8.85 (d, 1H, J=4.8 Hz), 8.49(d, 1H, J=8.7 Hz), 8.388.30 (m, 4H), 8.21 (dt, 1H, J=7.5, 2.1 Hz),8.01(s, 1H), 7.907.79 (m, 2H), 7.72-7.64 (m, 3H), 6.70 (s, 1H), 4.10 (s,31), 2.33 (s, 3H). Anal. (C₂₇H₂₀N₄O₂S. 1.3H₂O, 0.2EtOAc): Calc. C,62.15; H, 5.18; N, 15.64. Found C, 61.81; H, 5.01; N. 15.64.

Example 59(c)6[N-(5-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)-2-fluoro-4-methylphenyl)amino]-3-E-[2-(pyridin-2-yl]ethenyl]-1H-indazolehydrochloride

Example 59(c) was prepared in similar manner as Example 59(a) exceptthat Example 48(a) was used in place of Example 41 (a). Anal. Calc'd: C,63.21; H, 5.12; N. 18.43; Cl, 6.66. Found: C, 60.86; H, 5.38; N. 17.28:Cl, 6.52.

Example 59(d)6-[N-(3-((1,3-Dimethyl-1H-pyrazol-5-yl)carboxamido)-4-fluoro-phenyl)amino]-3-E-[2-pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

Example 59(d) was prepared in similar manner as Example 59(a) exceptthat Example 49(a) was used in place of Example 41(a). ¹H NMR (300 MHz,DMSO-d₆) δ: 13.2 (b, 1H), 9.97 (s, 1H), 8.75 (d, 1H, J=5.44 Hz), 8.51(bs, 1H), 8.35 (m, 2H), 8.20 (d, 1H, J=16.59 Hz), 8.06 (d, 1H, J=8.81Hz), 7.71 (d, 1H, J=16.59 Hz), 7.70 (m, 1H), 7.44 (dd, 1H, J=6.65 Hz,J=2.67 Hz), 7.24 (t, 1H, J=9.54 Hz), 7.12 (d, 1H, J=1.46 Hz), 7.05 (m,2H), 6.86 (s, 1H), 4.0 (s, 3H), 3.84 (bs, 1H), 2.20 (s, 3H).

Example 59(e)6-[3-((1-Ethyl-3-methyl-1H-pyrazol-5-yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazolehydrochloride

Example 59(e) was prepared in similar manner as Example 59(a) exceptthat Example 31(d) was used in place of Example 41(a). ¹H NMR (DMSO-4) δ13.53 (s, 1H), 1023 (s, 1H) 8.78 (d, 1H, J=5.5 Hz), 8.30 (m, 4H), 7.80(m, 2H), 7.59 (d, 1H, J=7.7 Hz), 755 (s, 1H), 7.41 (t, 1H, J=8.1 Hz),7.11 (s, 2H), 6.88 (d, 1H, J=6.7 Hz), 6.81 (s, 1H), 4.38(q, 2H, J=7.0Hz), 3.75 (bs, 1H), 2.19 (s, 3H), 1.29 (t, 3H, J=7.0 Hz). Anal. Calc forC₂₇H₂₅ClN₆O₂.1.7H₂O.0.1 EtOAc: C, 60.89; H. 5.45; N, 1555. Found: C,60.88; H, 551; N, 15.27.

Example 59(f)6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazolehydrochloride

Example 59(f) was prepared in similar manner as Example 59(a) exceptthat Example 33(a) was used in place of Example 41(a). Analyzed with2.0H₂O Calc'd C, 57.58; H, 5.05; N, 12.21; Cl, 6.99. Found: C, 57.24; H,5.048; N, 11.91: Cl, 6.63.

The exemplary compounds described above may be tested for their activityusing the tests described below.

Biological Testing: Enzyme Assays

The stimulation of cell proliferation by growth factors such as VEFG,FGF, and others is dependent upon their induction of autophosphorylationof each of their respective receptor's tyrosine kinases. Therefore, theability of a protein kinase inhibitor to block autophosphorylation canbe measured by inhibition of the peptide substrates. To measure theprotein kinase inhibition activity of the compounds, the followingconstructs were devised.

VEGF-R2 Construct for Assay: This construct determines the ability of atest compound to inhibit tyrosine kinase activity. A construct(VEGF-R2Δ50) of the cytosolic domain of human vascular endothelialgrowth factor receptor 2 (VEGF-R2) lacking the 50 central residues ofthe 68 residues of the kinase insert domain was expressed in abaculovirus/insect cell system. Of the 1356 residues of full-lengthVEGF-R2, VEGF-R2Δ507 contains residues 806939 and 990-1171, and also onepoint mutation (E990V) within the kinase insert domain relative towild-type VEGF-R2. Autophosphorylation of the purified construct wasperformed by incubation of the enzyme at a concentration of 4 μM in thepresence of 3 mM ATP and 40 mM MgCl₂ in 100 mM HEPES, pH 7.5, containing5% glycerol and 5 mM DTT, at 4° C. for 2 h. After autophosphorylation,this construct has been shown to possess catalytic activity essentiallyequivalent to the wild-type autophosphorylated kinase domain construct.See Parast et al., Biochemistry, 37, 16788-16801 (1998).

FGF-R1 Construct for Assay: The intracellular kinase domain of humanFGF-R1 was expressed using the baculovirus vector expression systemstarting from the endogenous methionine residue 456 to glutamate 766,according to the residue numbering system of Mohammadi et al., Mol.Cell. Biol., 16, 977-989 (1996). In addition, the construct also has thefollowing 3 amino acid substitutions: L457V, C488A, and C584S.

LCK Construct for Assay: The LCK tyrosine kinase was expressed in insectcells as an N-terminal deletion starting from amino acid residue 223 tothe end of the protein at residue 509, with the following two amino acidsubstitutions at the N-terminus: P233M and C224D.

CHK1 Construct for Assay: C-terminally His-tagged full-length human CHK1(FL-CHK1) was expressed using the baculovirus/insect cell system. Itcontains 6 histidine residues (6×His-tag) at the C-terminus of the 476amino acid human CHK1. The protein was purified by conventionalchromatographic techniques.

CDK2/Cyclin A Construct for Assay: CDK2 was purified using publishedmethodology (Rosenblatt et al., J. Mol. Biol., 230, 1317-1319 (1993))from insect cells that had been infected with a baculovirus expressionvector. Cyclin A was purified from E. coli cells expressing full-lengthrecombinant cyclin A, and a truncated cyclin A construct was generatedby limited proteolysis and purified as described previously (Jeffrey etal., Nature, 376, 313-320 (1995)).

CDK4/Cyclin D Construct for Assay: A complex of human CDK4 and cyclinD3, or a complex of cyclin D1 and a fusion protein of human CDK4 andglutathione-S-transferase (GST-CDK4), was purified using traditionalbiochemical chromatographic techniques from insect cells that had beenco-infected with the corresponding baculovirus expression vectors.

FAK Construct for Assay. The catalytic domain of human FAK (FAKcd49) wasexpressed using the baculovirus vector expression system. The 280 aminoacid domain expressed comprises residues methionine 409 to glutamate689. One amino acid substitution exists P410 relative to the sequenceassession number L13616 published by Whithey, G. S. et al., DNA CellBiol, 9, 823-30 (1993). The protein was purified using classicalchromatograph y techniques.

TIE-2 (TEK) Construct for Assay

The TIE-2 tyrosine kinase domain was expressed in insect cells as anN-terminal deletion starting from amino acid residue 774 to the end ofthe protein at residue 1124. This construct also carries a R774Mmutation, which serves as the initiating methionine residue intranslation.

VEGF-R2 Assay

Coupled Spectrophotometric (FLVK-P) Assay

The production of ADP from ATP that accompanies phosphoryl transfer wascoupled to oxidation of NADH using phosphoenolpyruvate (PEP) and asystem having pyruvate kinase (K) and lactic dehydrogenase (LDH). Theoxidation of NADH was monitored by following the decrease of absorbanceat 340 nm (e₃₄₀=6.22 cm⁻¹ mM⁻¹) using a Beckman DU 650spectrophotometer. Assay conditions for phosphorylated VEGF-R2Δ50(indicated as FLVK-P in the tables below) were the following: 1 mM PEP;250 μM NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mMpoly(E₄Y₁); 1 mM ATP; and 25 mM MgCl₂ in 200 mM HEPES, pH 7.5. Assayconditions for unphosphorylated VEGF-R2Δ50 (indicated as FLVK in thetables) were the following: 1 mM PEP; 250 μM NADH; 50 units of LDH/mL;20 units of PK/mL; 5 mM DTT; 20 mM poly(E₄Y₁); 3 mM ATP; and 60 mM MgCl₂and 2 mM MnCl₂ in 200 mM HEPES, pH 7.5. Assays were initiated with 5 to40 nM of enzyme. K_(i) values were determined by measuring enzymeactivity in the presence of varying concentrations of test compounds.The data were analyzed using Enzyme Kinetic and Kaleidagraph software.

ELISA Assay

Formation of phosphogastrin was monitored using biotinylated gastrinpeptide (1-17) as substrate. Biotinylated phosphogastrin was immobilizedusing streptavidin coated 96-well microtiter plates followed bydetection using anti-phosphotyrosine-antibody conjugated to horseradishperoxidase. The activity of horseradish peroxidase was monitored using2,2′-azinodi-[3-ethylbenzathiazoline sulfonate(6)] diammonium salt(ABTS). Typical assay solutions contained: 2 μM biotinylated gastrinpeptide; 5 mM DTT; 20 LM ATP; 26 mM MgCl₂; and 2 mM MnCl₂ in 200 mMHEPES, pH 7.5. The assay was initiated with 0.8 nM of phosphorylatedVEGF-R2Δ50. Horseradish peroxidase activity was assayed using ABTS, 10mM. The horseradish peroxidase reaction was quenched by addition of acid(H₂SO₄), followed by absorbance reading at 405 mm. K_(i) values weredetermined by measuring enzyme activity in the presence of varyingconcentrations of test compounds. The data were analyzed using EnzymeKinetic and Kaleidagraph software.

FGF-R Assay

The spectrophotometric assay was carried out as described above forVEGF-R2, except for the following changes in concentration: FGF-R=50 nM,ATP=2 nM, and poly(E4Y1)=15 mM.

LCK Assay

The spectrophotometric assay was carried out as described above forVEGF-R2, except for the following changes in concentration: LCK=60 nM,Mgcl₂=0 mM, poly(E4Y1)=20 mM.

CHK1 Assay

The production of ADP from ATP that accompanies phosphoryl transfer tothe synthetic substrate peptide Syntide-2(PLARTLSVAGLPGKK) was coupledto oxidation of NADH using phosphoenolpyruvate (PEP) through the actionsof pyruvate kinase (PK) and lactic dehydrogenase (LDH). The oxidation ofNADH was monitored by following the decrease of absorbance at 340 nm(ε340=6.22 cm⁻¹ mM⁻¹) using a BP8452 spectrophotometer. Typical reactionsolutions contained: 4 mN PEP; 0.15 mM NADH; 28 units of LDH/mL; 16units of PK/mL; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP; 25 mM Mgcl₂in 50 mM TRIS, pH 7.5; and 400 mM NaCl. Assays were initiated with 10 nMof FL-CHK1. K_(i) values were determined by measuring initial enzymeactivity in the presence of varying concentrations of test compounds.The data were analyzed using Enzyme Kinetic and Kaleidagraph software.

CDK2/Cyclin A and CDK4/Cyclin D Assays

Cyclin-dependent kinase activity was measured by quantifying theenzyme-catalyzed, time-dependent incorporation of radioactive phosphatefrom [³²P]ATP into a recombinant fragment of the retinoblastoma protein.Unless noted otherwise, assays were performed in 96-well plates in atotal volume of 50 μL, in the presence of 10 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (pH 7.4), 10mM MgCl₂, 25 μM adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 μg/mLleupeptin, 1 mM dithiothreitol, 10 mM β-glycerophosphate, 0.1 mM sodiumvanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis(β-aminoethylether)-N,N,N′N′-tetraacetic acid (EGTA), 2% (v/v) dimethylsulfoxide, and0.03-0.2 μCi [³²P]ATP. The substrate (0.3-0.5 μg) was purifiedrecombinant retinoblastoma protein fragment (Rb) (residues 386-928 ofthe native retinoblastoma protein; 62.3 kDa, containing the majority ofthe phosphorylation sites found in the native 106-kDa protein, as wellas a tag of six histidine residues for ease of purification). Reactionswere initiated with CDK2 (150 nM CDK2/Cyclin A complex) or CDK4 (50 nMCDK4/Cyclin D3 complex), incubated at 30° C., and terminated after 20minutes (min.) by the addition of ethylenediaminetetraacetic acid (EDTA)to 250 mM. The phosphorylated substrate was then captured on anitrocellulose membrane using a 96-well filtration manifold, andunincorporated radioactivity was removed by repeated washing with 0.85%phosphoric acid. Radioactivity was quantified by exposing the driednitrocellulose membranes to a phosphorimager. Apparent K_(i) values weremeasured by assaying enzyme activity in the presence of differentcompound concentrations and subtracting the background radioactivitymeasured in the absence of enzyme. The kinetic parameters (kcat, Km forATP) were measured for each enzyme under the usual assay conditions bydetermining the dependence of initial rates on ATP concentration. Thedata were fit to an equation for competitive inhibition usingKaleidagraph (Synergy Software), or were fit to an equation forcompetitive tight-binding inhibition using the software KineTic (BioKin,Ltd.). Measured K_(i) values for known inhibitors against CDK4 and CDK2agreed with published IC₅₀ values. The specific activity of CDK4 was thesame whether complexed to full-length cyclin D3 or the truncated CyclinD3 construct; both complexes also yielded very similar K_(i) values forselected inhibitors.

FAK Assay

FAK HTS utilized the fluorescence polarization assay provided by LJLBiosystems. The kinase reaction contained: 100 mM Hepes pH 7.5, 10 mMMgCl₂, 1 mM DTT, 1 mM ATP, and 1 mg/ml poly Glu-Tyr (4:1). The reactionis initiated by the addition of 5 nM FAKcd409. The reaction isterminated by the addition of EDTA followed by addition offluor-labelled peptide and anti-phosphotyrosine antibody, both providedby LJL Biosystems. Inhibition results are read on a Analyst (LJL)detector.

TIE-2 Spectrophotometric Assay

The kinase-catalyzed production of ADP from ATP that accompaniesphosphoryl transfer to the random copolymer poly(Glu₄Tyr) was coupled tothe oxidation of NADH through the activities of pyruvate kinase (PK) andlactate dehydrogenase (LDH). NADH conversion to NAD⁺ was monitored bythe decrease in absorbance at 340 nm (ε=6.22 cm⁻¹ mM⁻¹) using a BeckmanDU650 spectrophotometer. Typical reaction solutions contained 1 mMphosphoenolpyruvate, 0.24 mM NADH, 40 mM MgCl₂, 5 mM DTT, 2.9 mg/mLpoly(Glu₄Tyr), 0.5 mM ATP, 15 units/mL PK, 15 units/mL LDH in 100 mMHEPES, pH 7.5. Assays were initiated with the addition of 4 to 12 nMphosphorylated Tie-2 (aa 775-1122). Percent inhibition was determined intriplicate at a 1 μM level of inhibitor.

TIE-2 DELFIA Assay

Formation of phosphotyrosine was monitored using biotinylated p34cdc2(aa6-20=KVEKIGEGTYGVVYK) peptide as substrate. Biotinylated peptide wasimmobilized using NeutrAvidin™ coated 96-well microtiter plates followedby detection using anti-phosphotyrosine-antibody (PY20) conjugated toeuropium NI chelate. Typical assay solutions contained: 1 μMbiotinylated p34cdc2 peptide, 150 μM ATP, 5 mM MgCl₂, 1 mM DTT, 0.01%BSA, 5% glycerol, 2% DMSO, 25 mM HEPES pH 7.5. The assay was initiatedin the NeutrAvidin plate with 50 nM of TIE2 intracellular domain. Thekinase reaction was terminated with 50 mM EDTA. Plates were then washed,and europium antibody added. After incubation, they were again washed,and DELFIA™ Enhancement Solution added. Plates were read at standardEuropium time-resolved settings (ex 340 nm, em 615 run, delay 400 μsec,window 400 μsec). Percent inhibition was calculated with reference tointraplate wells which had added DMSO rather than compound in DMSO, withbackground subtracted from both experimental and control with referenceto an intraplate well which had EDTA added prior to addition of enzyme.

HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (“HUVEC”). HUVEC cells (passage 34, Clonetics, Corp.)were thawed into EGM2 culture medium (Clonetics Corp) in 175 flasks.Fresh EGM2 medium was added to the flasks 24 hours later. Four or fivedays later, cells were exposed to another culture medium (F12K mediumsupplemented with 10% fetal bovine serum (FBS), 60 μg/mL endothelialcell growth supplement (ECGS), and 0.1 mg/mL heparin).Exponentially-growing HUVEC cells were used in experiments thereafter.Ten to twelve thousand HUVEC cells were plated in 96-well dishes in 100μl of rich, culture medium (described above). The cells were allowed toattach for 24 hours in this medium. The medium was then removed byaspiration and 105 μl of starvation media (F12K+1% FBS) was added toeach well. After 24 hours, 15 μl of test agent dissolved in 1% DMSO instarvation medium or this vehicle alone was added into each treatmentwell; the final DMSO concentration was 0.1%. One hour later, 30 μl ofVEGF (30 ng/mL) in starvation media was added to all wells except thosecontaining untreated controls; the final VEGF concentration was 6 ng/mL.Cellular proliferation was quantified 72 hours later by MTT dyereduction, at which time cells were exposed for 4 hours MIT (PromegaCorp.). Dye reduction was stopped by addition of a stop solution(Promega Corp.) and absorbance at 595 λ was determined on a 96-wellspectrophotometer plate reader.

IC₅₀ values were calculated by curve-fitting the response of A⁵⁹⁵ tovarious concentrations of the test agent; typically, sevenconcentrations separated by 0.5 log were employed, with triplicate wellsat each concentration. For screening compound library plates, one or twoconcentrations (one well per concentration) were employed, and the %inhibition was calculated by the following formula:% inhibition=(control-test)÷(control-starvation)where

-   -   control=A⁵⁹⁵ when VEGF is present without test agent    -   test=A⁵⁹⁵ when VEGF is present with test agent    -   starvation=A⁵⁹⁵ when VEGF and test agent are both absent.        Cancer Cell Proliferation (MV522) Assay

The protocol for assessing cellular proliferation in cancer cells issimilar to that used for assessments in HUVEC cells. Two thousand lungcancer cells (line MV522, acquired from American Tissue CulturalCollection) were seeded in growth media (RPMI1640 medium supplementedwith 2 mM glutamine and 10% FBS). Cells are allowed to attach for 1 dayprior to addition of test agents and/or vehicles. Cells are treatedsimultaneously with the same test agents used in the HUVEC assay.Cellular proliferation is quantified by MTT dye reduction assay 72 hoursafter exposure to test agents. The total length of the assay is 4 daysvs. 5 for HUVEC cells because MV522 cells are not exposed to starvationmedium.

Mouse PK Assay

The pharmacokinetics (e.g., absorption and elimination) of drugs in micewere analyzed using the following experiment Test compounds wereformulated as a solution or suspension in a 30:70 (PEG 400: acidifiedH₂O) vehicle or as a suspension in 0.5% CMC. This was administeredorally (p.o.) and intraperitoneally (i.p.) at variable doses to twodistinct groups (n=4) of B6 female mice. Blood samples were collectedvia an orbital bleed at time points: 0 hour (pre-dose), 0.5 h, 1.0 h,2.0 h, and 4.0 h, and 7.0 h post dose. Plasma was obtained from eachsample by centrifugation at 2500 rpm for 5 min. Test compound wasextracted from the plasma by an organic protein precipitation method.For each time bleed 50 μL of plasma was combined with 1.0 mL ofacetonitrile, vortexed for 2 min. and then spun at 4000 rpm for 15 min.to precipitate the protein and extract out the test compound. Next, theacetonitrile supernatant (the extract containing test compound) waspoured into new test tubes and evaporated on a hot plate (25° C.) undera steam of N₂ gas. To each tube containing the dried test compoundextract 125 μL of mobile phase (60:40, 0.025 M NH₄H₂PO₄+2.5 mL/LTEA:acetonitrile) was added. The test compound was resuspended in themobile phase by vortexing and more protein was removed by centrifugationat 4000 rpm for 5 min. Each sample was poured into an HPLC vial for testcompound analysis on an Hewlett Packard 1100 series HPLC with UVdetection. From each sample, 95 μL was injected onto aPhenomenex-Prodigy reverse phase C-18, 150×3.2 mm column and eluted witha 45-50% acetonitrile gradient run over 10 min. Test-compound plasmaconcentrations (μg/mL) were determined by a comparison to standard curve(peak area vs. conc. μg/mL) using known concentrations of test compoundextracted from plasma samples in the manner described above. Along withthe standards and unknowns, three groups (n=4) of quality controls (0.25μg/mL, 1.5 μg/mL, and 7.5 μg/mL) were run to insure the consistency ofthe analysis. The standard curve had an R2>0.99 and the quality controlswere all within 10% of their expected values. The quantitated testsamples were plotted for visual display using Kalidagraph software andtheir pharmacokinetic parameters were determined using WIN NONLINsoftware. Example 1(a) provided the following results: 0.69 (Mouse pK,AUC, ip, μg-h/ml); 0.33 (Mouse pK, AUC, po, μg-h/ml).

Human Liver Microsome (HLM) Assay

Compound metabolism in human liver microsomes was measured by LC-MSanalytical assay procedures as follows. First, human liver microsomes(HLM) were thawed and diluted to 5 mg/mL with cold 100 mM potassiumphosphate (KPO4) buffer. Appropriate amounts of KPO4 buffer,NADPH-regenerating solution (containing B-NADP, glucose-6-phosphate,glucose-6-phosphate dehydrogenase, and MgCl₂), and HLM were preincubatedin 13×100 mm glass tubes at 37 C. for 10 min. (3 tubes per testcompound—triplicate). Test compound (5 FM final) was added to each tubeto initiate reaction and was mixed by gentle vortexing, followed byincubation at 37° C. At t=0, 2 h, a 250-μL sample was removed from eachincubation tube to separate 12×75 mm glass tubes containing 1 mLice-cold acetonitrile with 0.05 μM reserpine. Samples were centrifugedat 4000 rpm for 20 min. to precipitate proteins and salt (BeckmanAllegra 6KR, S/N ALK98D06, #634). Supernatant was transferred to new12×75 mm glass tubes and evaporated by Speed-Vac centrifugal vacuumevaporator. Samples were reconstituted in 200 IAL 0.1% formicacid/acetonitrile (90/10) and vortexed vigorously to dissolve. Thesamples were then transferred to separate polypropylene microcentrifugetubes and centrifuged at 14000×g for 10 min. (Fisher Micro 14, S/NM0017580). For each replicate (#1-3) at each timepoint (0 and 2 h), analiquot sample of each test compound was combined into a single HPLCvial insert (6 total samples) for LC-MS analysis, which is describedbelow.

The combined compound samples were injected into the LC-MS system,composed of a Hewlett-Packard HP1100 diode array HPLC and a MicromassQuattro II triple quadruple mass spectrometer operating in positiveelectrospray SIR mode (programmed to scan specifically for the molecularion of each test compound. Each test compound peak was integrated ateach timepoint. For each compound, peak area at each timepoint (n=3) wasaveraged, and this mean peak area at 2 h was divided by the average peakarea at time 0 hour to obtain the percent test compound remaining at 2h.

The results of the testing of the compounds using various assays aresummarized in the table below, where a notation of “% @” indicates thepercent inhibition at the stated concentration, “*” values represent Ki(nM) or % inhibition at a compound concentration of 1 μM for * or 50 nMfor **, unless otherwise indicated. “NI” indicates no significantinhibition

TABLE 1 HUVEC + % HUVE albumin MV522 remain FLVK FLVK- Lck- CHK- FGF-CDK2 CDK4 C IC50 IC50 IC50 (HLM, Ex # ** P** P* 1* P* * * (nM) (nM) (μM)2 h)  2(b)  300 425   549   228 μM 2,200 8,000  2(c) 2600   50 μM   26μM  1(a)   0.3  2  88    5.2    27   19   13    54    0.35  98  3   6.6 65  37%    4.8   112   16   23    930    2.2  8(a)   3.2  23  43%   530   42  >100 μM  >100 μM >1000 >10  8(b)  72    12% @ 50 μM  2(d)   3.7 43%    91    68   53   53    450    0.18  1(c)   1.4  4.7  46%    78  560   670 >1000 >10  2(a)  40    61%   610  1600 >1000    0.58 @20 μM 1(b)   2.2   1400  4000  1300 >1000 >10  8(c)   2.6  16  34%    >10,000 >100 μM  >100 μM    280 >10  9(a)   2.4  16 162   400  1700   870 >10 9(b)  24   448  2(e)  40    5% @    20 μM 10   9   9100  >700 >10 20(a) 29  12.7    200    9.4  52 20(b)   1.6  8  23%    28%     8.2 Ca. 10 14 15    12% @25 μM  7  18  1,300 17  11   532  8(b)  11 82,000  4(a)  0.65  1.4  68% NI    15.4 NI   19%     3  30    6.3  35 23   1.6  2.1 12% NI    14% NI   17%     9.5  106    5.7  74 21   4.6  >700 11 1234,000 22(b)   0.63  1.2    21.5     4.8    85 22(a)   0.22  0.2   12 >10 22(c)   0.64    38  4(b)   2.7  1.9  13%    4.9    25  205   3.2  63 @ 1 μM 12(a)   1.8  6.9  17%    19     6  87    2.1  59 12(b)  0.48  1.8  32%    31     4.8  44 >10  29 18  12.5 19(b)   0.49  6.6 58% NI    60% NI   11%     2.9  27    4.3 137 19(a)  13.8  6.8  16%   92%    44 @ 1 μM 19(c)  5.9  50%    68%    17 12(c)   1.6 19(d)  0.72  33%    39%     6.8  34 >10  36  5(a)   0.03  28%    10.4    12   9.6 12(d)   0.39  31%    61%     8.1 >10  51 13   1.3  61%    74%    3.9  28 >10  69 15  15 16(a)   0.08  28% NI    65% NI NI     4.5 112    8  7*  6(a)   0.74  33%    67%     8.5  50    3.5  69*  5(b)  0.9  78%    14     3.7  33    8.5 16(b)   0.34  22%    73%     4.7 140 >10  50 16(c)  1.1    100- >10   1000 16(d)   0.43  33%    90%   11 >10 16( )   1.3  8%    59%     4.9  106 >10  40  6(b)  0.15  81%   95%     8  60    4 128 16(f)  2.8  >30 >10 19(e)  20  >300 30(a)  1.7  45%    94%     1.6  22    5.7  64 19(f)   0.18  52%    58%    2.3  16    3.9  98 46  3.5 19(g) 30(b)  2.2    90 19(q)   0.86  19%   59%    18 1920  90 30(c)   0.83  44%    82%     2.5  21  54 19(h) 5.9    600    7.9 44  9.6  >700 38(a)   0.22  77%    74%     4.5  20  10.7  72 45(b)  99%  86%    79%     1.9  11.5    4.4  97 45(a)   0.062    3.1 ca. 15    3.5  97 19(l)  4.7  >300 42(a)   0.046  79%  53    65    0.8   8    5.5  92 38(b)  72%    79 19(j)   0.33  23%    44%     2.2 50 >10  66 42(b)   0.35  75%    27%     2.1  29    2.1  81 19(k)  100% 37%    41%     2.6  28    4  58 33(b)   0.66  76%  63%    77%     0.8 11.5   15  45 26  1.1    6.6    3.2 19(l)   0.72  36%    88%     6.8 100    3.8 19(m)   0.68  35%    23%  94 >10  61 33(a)   3.8  42%  9%   0    56    2%    7%     0.5   2.7 >10  29 19(n)   0.54  26%    48%    3.4  23    2.9 33(c)   0.28  26%    76%   6.6 >10  16 33(d)   0.14 55%    24 >300    8  22 40(a)  17.9 41(aa)   0.11  49%    37%     1  5.2 >10 100 41(b)   0.26  24%    31%     2   9.8 >10  80 (UV) 42(e)  1.1  95 42(d)   1.7  44 >10 43   2.6  56%  24  2 19(o)  89%  20 41(c)  0.22  83%  36%    77%     0.4   5.3  68 41(d)   0.093     0.9  6.441(a)   0.03  94%  50%    0    20    0    6%     0.48   4.4 >10  9619(p)   1.5 41(e)   0.22  21%    31%     0.15   5.6,  22   6.1 41(f)  0.11  84%  65%    92%     0.45  20  59 41(g)   0.1  36%    95%    0.9 >10  52 30(d)   0.37   3.8 30(e)   0.37  62%    92%  29 33(e)  1.7  70%  2%     68%     0.46   5 >10  54 33(f)   8  17  31 41(h)  90%  30%     2  25  8 47   0.25  50%    88% 31(a)   0.29  77%*    95%    0.7  10  58 41(l)   0.04  38%*    76%     0.25   3.3  48 35(u)  79%  2.8  27 32(a)   <0.1  86%*    96%     0.16   4.5  2 41(k)   2.95  20%   49%  48 41(l)   0.24  63%*    66%  386 41(m)   0.75  40%    67%  23 0 41(n)   0.2  66%*    87%  28  70 31(b)   <0.1  66%    97%     5.6  241(o)   0.05  77%    74%  10  94 31(c)   <0.1  81%    98%  11.4  8735(gg)  23% >100 33(g)  15% 34  97%  78%    95%  15  28 50 35(v)  72% 11%    59%  22  26 35(w)  59%  35 35(x)  75%   2  37 35(a)  76%  12%   59%   2.1  33 35(b)  49%  12%    59%  35 35(c)  76%  11%    42%   6.3 17 41(p)   0.06  49%    0    90    6%    3%     0.27   2.6 >10  6242(c)  95%   1 to 3 41(dd)  98%  50%    69%   5.8  7 41(bb)  99%  76%   88%   1 to 3 110 35(y)  99%  29%    82%   1 to 3  7 35(d)  76% >10031(d)  96%  52%    0    14    5%    9%    1.3 ca. 13    5.2 110 41(q) 100%  53%    91%   2.7 35(e)  99%  56%    69%   4.8 >10  34 35(f)  100%  8  15 35(g)  100% ca. 15  53 35(h)  100%   3.6  9 35(i)  100%   4.735(j)  99%   1.5  5 35(k)  85%  6%    0    34%    8%    7%   2.2 >10  1441(ee)   0.13  13%    0    94%    0    2%    0.24   4.3,    9.4  47 2.735(z)  95%   7.1  2 35(aa)  99%   5  15 41(r)  100%  55%    0    92%   0    5%  11  83 41(cc)  97%  41%   95% >100 35(l)  90%  12 35(cc) 89%  15%    0    74%    5%    6%    0.05   1.6  31 35(ee)  82%   3  1335(ff)   0.11  25%    75%   5.8  31 35(dd)   0.6  17%    0    75    7%   8%    0.18   2.9 >10  26 35(bb)  87%   4.1  8 32(b)   0.08  70%   95%  21 >10 35(hh)  100%  34%    73%   7 35(m)   0.04  61%    82%  3548(a)   0.37  13%    0    14    0    0   8.8  55 39(a)  53%    1.4 ca.50  70 35(n)   0.83  58%    23%    92    4%   10%    0.11  11    5.1  4741(s)   0.23  53%    86% 35(o)  39%  17%    44% >100 41(t)   0.06  51%   0    85%    1%    2%   3.8  87 32(c)   0.27  52%    96%   >30 36(b) 85%  22%    43%   >30 37(d)  26%  10%    38% >100 37(c)  83%  12%   39%  12  21 37(b)  48%  8%    36%  30-  100 59(a) 41(u)   0.08  54%   74%   7.9 41(hh)  98%  13%    74%   3.9  72 36(c)  89%  28%    60%  >30 36(a)  87%  19%    38%  19  58 35(p)  62%  5%    11%   >30 35(q) 92%  42%    51%  18 40(b)  89%  32%    92% 41(ff)  98%  15%    12   5.6 68 37(a)  57%  6%    35%  15  21 41(v)  68%*  52%    68%  12 41(ii) 57%  18%    11  13  85 35(r)   0.11  16%    20    0.36   2.3 >10  5135(s)  60%*  18%    64%   4.6  16 35(t)  59%*  12%    63%   4  7 41(ll) 95%  14%    91%  23 41(w)  97%  49%    67% ca. 10 41(x)  98%  66%   3.4   4.6 100 41(mm)  93%  6%    46%    1.3  14.4  94 41(jj)  87% 19%    81%  21 41(y)  98%  61%    86%  30- 100 31(e)   0.02  43%    62%  6.2    8.6  49 40(c)  24%  28%    59% 41(gg)  84%  27%    3.5   9.5 50 41(nn)  57%  7%    91% >100 41(j)  98%  16%    41%   7.7 48(b)  97% 6%    77% ca. 8 41(z)  100%  54%    74%   7.5 41(kk)  100%  26%    97% 16  63 39(b)   2.8  10%    50%   >10  67 31(f)  97%  62%    99%   >1059(b) 49(a)   0.04  11%    79 ca. 4    8.4 59(c) 49(b)  98%  9%    80%ca. 10 56   5% 35(ii)  44% 59(d) 57  100%  30%    89% 59(e) 58  98%  19%   98%

TABLE 2 HCT-116 IC50 Ex # CDK2* CDK4* CHK1* FLVK-P* Lck* FGF* (μM) 24(a) 0.017  0.0051  0.028  0.0983 67% 72% 0.23 24(b)  0.021  0.0032  0.02 0.0331 96% 88% 0.37 24(c)  0.0034  0.0015  0.044  0.0142 93% 89% 0.4424 17% 16% NI @ (m) 20 μM 24(l)  0.086  0.071 62% @ 3.8 20 μM 24(d) 0.083  0.017  0.056  0.125 51% 66% 0.023 24(e)  0.03  0.0044 75% 52%0.15 24(f)  0.0072  0.0074 97% 89% 1.5 24(g)  0.13  0.029  1.67 0.194 >5 24(o)  0.029  0.2 2.2 24(h)  0.054  0.053 3.6 24(l)  0.055 0.013 1.7 24(j)  2.1  0.32 24(k)  0.056  0.0072 81% 89%  0.16 0.2 25(a) 0.08  0.021 49% 44% 62% 0.051 24(n)  0.035  0.019 1.5 25(b)  0.112 0.048 83% 87% 87% 2.1 25(c)  0.233  0.0155 90% 96% 0.25 25(d)  0.16 0.098 87% 60% 80% 25(e)  0.477  0.181 16% 13% 26% 25(f)  0.39  1 NI 58%56% 0.098 25(g)  0.08  0.021 21% 76% 82% 2 25(h)  0.17  0.024 86% 87 910.32 25(l)  0.021  0.02 >5 24(p)  0.089  0.092 0.44 25(j)  0.079  0.01670 0.0083 *values represent Ki (μM) or % inhibition at a compoundconcentration of 1 μM, unless otherwise indicated. NI indicates nosignificant inhibition

TABLE 3 Example # CHK-1* CDK1* CDK2* CDK4* FLVK* 28(d) 0.018 93% 66% 87%27(j) 15% @ 50 uM 27(a) 0.198 NI @ 1 NI @ 100 28% @ 5 71% μM μM μM 27(b)28% @ 50 μM 28(a) 0.108 77% 75% 79% 84% 27(c) 11% @ 5 μM 28(b) 0.014397% 98% 96% 27(d) 14% @ 10 μM 27(e) 0.757 34% 27(l) 0.227 85% 73% 92%27(f) 0.35 0.223 3.3 0.78 49% 27(h) 0.311 84% 27(k) 24 28(c) 1.14 34%27(g) 0.85 52(b) 0.08 0.041 0.241 0.117 94% 55 10 52(a) 0.263 39% 60%53(a) 0.301 24 13% @ 5 28% @ 5 μM μM 29(b) 0.138 0.9 3 3.9 29(a) NI @ 25μM 29(c) 0.174 56% 2.2 2 29(d) 10 29(e) 0.074 0.593 1.4 2 33% 29(f)0.418 51 0.087 0.146 84% 79% 29(r) 0.072 0.066 1.3 1.1 29(g) 0.068 0.391.4 1.1 29(h) 0.14 1.3 3 2.2 54(d) 0.68 NI @ 1 μM 54(b) 3.1 29(l) 0.10426% 3.1 5 53(d) NI @ 100 μM 54(e) 0.342 NI @ 1 μM 54(a) 0.896  1% 53(c)1.1 29(j) 0.533 31% 29(q) 11 11% 29(p) 0.232  6% 53(b) 1.4 29(k) 1.354(f) 2.9 54(c) 0.125 NI 54(g) 0.195  3% 29(o) 46 53(e) 0.886 13% 29(l)1.4  7% 29(n) 16 29(m) 1 54% 53(f) 7.3 54(h) 1 29(s) 11 54(j) 0.42454(i) 0.461 29(t) 0.072 29(u) 0.151 53(g) 1.5 54(l) 0.99 54(k) *valuesrepresent Ki (μM) or % inhibition at a compound concentration of 1 μM,unless otherwise indicated. NI indicates no significant inhibition

Library Example I

The three library building blocks (“amine templates”)6-(3-aminophenoxy)-3-E-styryl-1H-indazole (Y=0),6-(3-aminobenzoyl)-3-E-styryl-1H-indazole (Y═CO), and6-(3-aminophenyl)amino-3-E-styryl-1H-indazole (Y═NH) were prepared asdescribed in Example 7, Example 18, and Example 46 respectively. 0.1 Msolutions of the acid, the amine template,o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate and triethylamine were prepared separately inanhydrous DMF. To each tube in an array of 8×11 culture tubes (10×75 mm)was added 105 μL (0.0105 mmol) of a different acid. To this was added100 μL (0.01 mmol) of the amine solution, 105 μL (0.0105 mmol) of thetriethylamine solution followed by 105 μL (0.0105 mmol) of theo-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate solution. The reactions were stirred in a heatingblock at 50° C. for 3 h. The reaction mixtures were transferred to a 1mL 96-well plate using a liquid handler. The solvents were removed usingthe SpeedVac™ apparatus and the crude reaction mixtures were redissolvedin DMSO to give a final theoretical concentration of 10 mM.

The compounds in the table were tested for inhibition of theproliferation of HUVEC at a nominal concentration of 10 nM, and theresults are listed in Table I below, calculated from:% inhibition=(control-treated)/(control-starvation)×100Under these testing conditions, >50% inhibition is consideredsignificant.

TABLE I LIBRARY Y = Y = R⁸ CO Y = O NH

134 127 135

124 145 118

128 94 115

134 138 112

3 56 111

30 91 109

101 157 105

−62 5 105

108 115 104

124 147 103

125 124 103

158 131 101

142 101 98

137 137 95

131 68 94

58 68 94

75 78 87

113 150 86

72 87 85

128 92 81

113 30 80

51 35 79

125 122 78

87 80 77

26 52 76

99 52 75

54 85 71

80 91 64

71 52 60

21 76 43

81 93 40

87 86 34

25 70 32

2 52 30

24 96 30

35 64 30

37 48 30

57 70 29

52 42 27

47 69 25

51 71 25

35 57 24

18 51 23

45 57 23

19 22 20

32 32 20

10 24 20

24 45 19

−13 18 17

−36 −6 17

−2 25 17

3 24 16

5 25 16

−1 30 15

33 42 13

3 36 13

14 90 12

−37 25 11

81 64 11

47 17 10

27 30 10

5 23 7

21 40 7

50 112 6

96 134 6

42 13 6

−20 25 6

44 82 5

33 32 3

0 4 2

20 43 0

8 23 0

28 80 −1

10 19 −2

12 40 −3

3 46 −3

39 −4

37 20 −5

−11 52 −7

10 59 −7

27 48 −8

64 83 −8

35 42 −9

27 52 −9

31 20 −17

56 17 −17

−20 18 −18

64 38 −20

Library Example II

(a) When Y═S in Formula I

6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole(Y═S) was prepared as decribed in Example 35(a). Solutions of 261 amines(1.5 pmol), and Et₃N (0.1393 μL, 1.0 μmol), dissolved in DMF (15 μL),were distributed in to the wells of a 96-well plate. In cases where theamine was used as a hydrochloride salt, additional Et₃N (0.4179 μL, 3.0μmol) was added to liberate the free base. Each of the wells was treatedwith a solution of pentafluorophenyl ester (0.5395 mg, 1.0 μmol)dissolved in DMF (30 μL), then agitated for 24 h at room temperature.The crude reaction mixtures were concentrated using a GeneVac™apparatus, and then diluted with DMSO to a final concentration of 10 mM.(b) When Y═NH in Formula I

Solutions of 263 amines (2.0 μmol), and Et₃N (0.4181 μL, 3.0 μmol) weredissolved in DMF (20 μL) and distributed into the wells of a 96-wellplate. In cases where the amine was used as a hydrochloride salt,additional Et₃N (0.5575 μL, 4.0 μmol) was added to liberate the freebase. Each of the wells were treated with a solution of:6-[2-carboxyphenyl-amino]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole(0.447 mg, 0.75 μmol) dissolved in DMF (20 μL), followed by a solutionof HATU (0.570 mg, 1.5 μmol) dissolved in DMF (10 μL), and then agitatedfor 72 h at room temperature. The crude reaction mixtures wereconcentrated using a GeneVac™ apparatus, and then diluted with DMSO to afinal concentration of 10 mM.

The compounds in the Library Table II were tested for inhibition of theproliferation of HUVEC at a nominal concentration of 0.5 and 2 nM forY=S and the results are listed in below, as calculated from:%inhibition=(control-treated)/(control-treated)/(control-starvation)×100Under these testing conditions, >50% inhibition is consideredsignificant

TABLE II LIBRARY R¹ 0.5 nM 2 nM

19 89

38 2

37 16

39 15

35 10

32 31

5 14

14 55

23 44

25 35

30 23

5 19

70 105

25 15

44 19

38 5

23 6

4 20

21 60

34 61

23 23

26 37

2 6

32 24

32 6

48 8

45 88

17 4

8 21

15 27

22 24

22 23

16 20

10 24

28 22

37 12

49 91

40 31

18 32

6 43

30 78

34 58

22 20

19 28

6 1

20 10

31 3

32 10

31 −1

6 4

4 29

23 61

18 24

21 15

−1 26

−6 0

18 5

23 17

20 2

37 15

0 4

5 1

8 18

3 15

23 16

42 22

−9 1

25 −5

16 7

27 2

49 −9

18 40

5 9

8 23

16 21

13 23

8 22

2 −19

17 1

7 −1

5 −6

26 −19

23 −32

2 −3

18 25

1 13

4 4

18 22 H-X1 9 30

7 25

16 17

13 31

95 106

59 97

30 86

22 43

33 64

28 29

31 20

42 80

25 53

65 110

29 58

52 107

31 36

4 10

8 23

13 20

33 18

20 25

62 99

6 16

17 13

19 22

39 18

44 5

43 96

19 55

29 92

49 109

25 14

24 84

19 24

47 107

35 40

26 31

53 75

8 21

70 112

72 109

26 31

28 14

−6 41

12 76

33 94

27 17

44 28

55 50

21 90

12 53

21 64

35 63

21 −5

1 65

28 103

51 105

44 97

44 40

47 −4

47 89

12 29

44 100

35 69

16 2

32 92

92 103

9 1

56 96

26 2

39 13

19 5

24 31

35 106

15 36

69 59

−11 42

16 42

15 95

20 92

19 −1

31 30

−1 14

9 34

6 44

1 52

18 −2

9 −9

40 94

38 68

25 40

34 99

30 94

24 99

19 101

20 92

15 99

16 37

17 23

70 111

60 99

75 114

81 95

24 86

−3 64

26 71

14 60

51 108

8 37

15 23

20 32

35 63

28 47

26 16

18 11

13 7

28 69

18 43

11 47

19 86

26 83

50 111

45 103

53 95

31 108

69 104

36 106

58 100

63 104

12 55

16 73

18 −3

16 17

32 35

36 66

68 49

26 39

15 4

25 31

65 90

21 39

10 29

16 2

22 36

18 29

25 25

27 80

30 70

10 23

50 40

51 67

23 51

31 66

86 107

46 103

26 59

30 61

41 16

15 8

74 101

78 60

58 37

34 90

34 69

19 35

15 −1

11 15

15 −9

12

8

38

48

Library Example III

0.1 M solutions of the amines, triethylamine and 4-dimethylaminopyridinewere prepared separately in anhydrous DMF and transferred to a glovebox.0.1 M solution of6-[2-carboxy)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-1H-indazole,Example 33(g), tetrabutylammonium salt ando-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate was prepared in the glovebox. To each tube in anarray of 8×11 culture tubes (10×75 mm) in the golvebox was added 100 μL(0.01 mmol) of the different amine solutions followed by the addition of100 μL (0.01 mmol)tetrabutylammonium2-{3-[(E)-2-(2-pyridinyl)ethyly]-1H-indazol-6-yl}sulfanyl)benzoatesolution, 100 μL (0.01 mmol) of the triethylamine solution, 100 μL (0.01mmol) of the 4-dimethylaminopyridine solution and 100 μL (0.01 mmol) ofthe o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate solution. The reactions were stirred in a heatingblock at 50° C. for 1 h. The reaction mixtures were transferred to a 1mL 96-well plate using a liquid handler. The solvents were removed usingthe SpeedVac™ apparatus and the crude reaction mixtures were redissolvedin DMSO to give a final theoretical concentration of 10 mM.

The compounds in the table were tested for inhibition of theproliferation of HUVEC at a nominal concentration of 0.5 nM, and theresults are listed in Table m below, as calculated from:% inhibition=(control-treated)/(control-starvation)×100Under these testing conditions, >30% inhibition is consideredsignificant.

TABLE III LIBRARY R % inhibition

−1

−17

4

17

6

22

−19

9

2

5

15

−22

−19

−9

−11

−17

−6

−11

−1

12

9

7

−32

−22

−15

−22

−4

4

−29

−6

−8

8

1

−38

−36

−11

−14

−20

−5

−43

−5

0

6

0

−28

−13

−21

−15

0

−18

−15

−1

−11

3

1

−27

−47

33

17

20

−29

−17

−7

0

−1

4

−43

−42

22

13

81

−23

−31

−3

0

3

13

0

−113

2

4

20

2

−3

−9

−9

−1

4

12

9

−6

−2

5

6

18

20

−23

−12

22

9

7

−4

4

7

7

18

11

−31

−22

−5

−1

−7

−22

−3

11

4

20

15

−45

−37

−20

−4

0

−29

−26

3

8

12

6

−57

−25

−41

−21

−28

−20

−20

3

11

1

−5

−60

−46

−22

−20

−7

−28

−10

−13

13

−7

−13

−45

−40

−2

−11

−31

−30

−11

−2

18

7

1

0

0

24

14

61

9

1

1

4

1

8

−15

−12

52

19

13

−7

−26

7

9

18

10

−37

−2

43

5

1

−3

−13

−1

−1

16

4

−23

−20

−15

10

−18

−9

29

1

10

0

9

−3

−11

22

9

−5

−19

−6

−12

−1

−7

2

−34

−13

13

48

36

−8

−11

1

−4

10

−1

−33

−19

−6

2

−21

−16

−25

−9

1

4

37

−12

−20

−22

7

−22

−12

0

−6

13

−1

−11

11

15

−8

1

3

9

2

8

15

14

3

−31

−2

11

13

10

3

6

2

−1

3

18

−17

−8

3

0

18

7

−6

2

3

14

10

−20

−10

4

10

9

−7

−3

4

8

10

7

−9

46

2

23

11

−10

−4

7

9

10

15

−18

−3

−2

5

−13

−9

−2

−6

17

19

18

−24

0

−6

3

−20

−16

−19

1

3

6

18

−18

−9

2

14

−10

−7

4

11

11

8

23

1

−20

0

57

24

1

−10

−8

−2

5

3

TABLE 4

R CHK-1 @ 20 μM

30.6

28.3

22.5

21.7

40

27.8

20.2

57.7

35.5

24.2

31.1

13.7

23.9

48.6

19.5

32.3

24.9

25.8

94.9

38.7

72

21.1

31.4

28.3

28.5

28.1

25.7

23.9

36.3

45.4

32.7

24.7

52.7

38.6

23.6

39.8

28.1

33

52.4

38.6

32.3

42.9

24.1

31.6

TABLE 5 % Inhibition @ 1 μM Example # Tie2-P FAK 41(a) 50   5  41(ee)41   7  41(p) 49   9  41(r) 56   5  41(t) 51   9  48(a) 52  11  31(d)46   6  33(a) 35  12  35(k) 55   7  35(dd) 48   4  35(n) 82   1  35(cc)47   7   1(a) 95* 69*  3     NI* 26*  8(a) 55*  3*  2(d) 90* NI*  8(c)31* 15*  9(b) 88* NI* 10     20* NI* 17     50   4(a) 69  11     40  4(b) 29   2(c) NI  22(a)  8  23      5  22(b) NI  21     27  12(a) NI 19(a) 18  19(c) NI  12(c) 17  19(d) 15   5(a) 44  16(a) 10  16(b) 52 24(a) 91* 24(b) 92* 24(c) 94  30(a) 19   8(d) 10  *compound tested at 10μM values in bold refer to spectrophotometric assay results; non-boldedvalues were obtained in a DELFIA assayDetermination of Inhibitor Concentration in Mouse Plasma afterIntraperitoneal and Oral Dosing

The dosing solution consisted of the inhibitor dissolved in one of thefollowing vehicles: either 30% or 60% aqueous polypropylene glycolsolution with a molar equivalent of HCl in water, or 0.5%carboxymethylcellulose in water. The final concentration was normally 5mg/ml with a dosing volume of 5 or 10 ml/kg. Taconic (Germantown, N.Y.)female mice were dosed as a function of compound mass per body mass,usually 50 or 25 mg/kg. Blood collection was via ocular bleed at 0.5, 1,4 hr with the final time point, 7 hour, via intracardiac puncture. Theblood was centrifuged to collect plasma, which was then stored at −80°C. until analysis. Samples were prepared for analysis using an internalstandard and sodium hydroxide. After vortexing, ethyl acetate was addedand mixed for 15-20 minutes at ambient temperature. Followingcentrifugation, the resulting organic layer was evaporated andsubsequently reconstituted in acetonitrile and buffer. The samples werethen analyzed via HPLC or LC-MS.

Compound levels were quantitated by generating a standard curve of knowncompound concentration in mouse plasma. Compound levels were plotted asa function of time and analyzed to provide area under the concentrationcurve (AUC ng*hr/ml), maximum concentration (Cmax ng/ml), minimumconcentration (Cmin or 7 hour trough ng/ml), and terminal half-life (T½hr). The results are shown in Table 6.

TABLE 6 Cmin (7 Vehicle Example Dose AUC_(last) Cmax hr conc.) T_(1/2 β)PEG400:H2O # Route mg/kg (ng*hr/ml) (ng/ml) (ng/ml) (hr) pH 2.3  1 (a)IP 50 691 283 2.4 30:70 19 (b) PO 50 NA 30 ∞ 60:40 19 (j) IP 25 232055764 456 1.6 60:40 19 (j) PO 50 5889 1937 63 1.2 60:40 19 (k) IP 25 428149 15 2.2 60:40 19 (k) PO 50 19 8 4 2.2 60:40 31 (a) IP 25 47538 130181906 2.4 30:70 31 (a) PO 50 40863 14499 834 1.6 30:70 31 (b) IP25 >7037 >2000 177 1.7 30:70 31 (b) PO 50 2071 1100 15 1.0 30:70 31 (d)IP 25 237784 64184 15073 5.3 30:70 31 (d) PO 10 49120 9740 2022 3.130:70 31 (d) PO 25 203860 50810 3801 1.9 30:70 31 (d) PO 50 430683 7691542478 39.3 30:70 31 (e) PO 25 >30339 >5000 2952 13.1 30:70 31 (f) PO25 >244545 >50000 9521 2.6 30:70 32 (a) IP 25 >20554 >4000 1273 3.730:70 32 (a) PO 50 4190 1746 40 1.1 30:70 32 (b) PO 25 490 179 18 2.130:70 32 (c) PO 25 388 161 10 2.4 30:70 33 (a) IP 25 13813 13794 54 1.130:70 33 (a) PO 100 3556 90 0.5% CMC 33 (a) PO 25 721 66 0.5% CMC 33 (a)PO 50 19067 23562 25 0.8 30:70 33 (b) IP 25 11245 1990 902 3.0 60:40 33(b) PO 50 3925 1496 76 3.0 60:40 33 (c) IP 25 697 505 7 1.2 30:70 33 (c)PO 50 183 94 5 3.0 30:70 33 (d) IP 25 5080 1738 113 1.6 60:40 33 (d) PO50 4744 1614 8 0.9 60:40 33 (e) IP 25 14323 9938 94 1.0 30:70 33 (e) PO50 13290 9967 12 0.7 30:70 33 (f) IP 25 1887 1699 6 2.4 30:70 33 (f) PO50 1436 1186 3 0.7 30:70 35 (a) IP 25 2032 2138 24 1.4 30:70 35 (a) PO50 2445 1780 10 0.9 30:70 35 (aa) PO 25 4036 4168 106 2.1 30:70 35 (b)IP 25 2840 1509 12 0.8 30:70 35 (b) PO 50 4048 5595 13 0.8 30:70 35 (c)IP 25 9408 1976 465 3.2 30:70 35 (c) PO 50 4744 909 321 4.9 30:70 35(cc) IP 25 2223 3183 6 1.4 30:70 35 (cc) PO 50 1718 1439 5 0.9 30:70 35(dd) IP 25 >23046 >4000 1364 4.1 30:70 35 (dd) PO 25 1360 444 58 2.00.5% CMC 35 (dd) PO 25 >6521 >4000 114 1.4 30:70 35 (e) IP 25 2409 127265 1.8 30:70 35 (e) PO 50 1503 1043 6 0.9 30:70 35 (ee) IP 25 546 579 21.5 30:70 35 (ee) PO 25 157 77 9 14.6 30:70 35 (f) IP 25 397 131 25 3.830:70 35 (f) PO 50 358 93 27 3.6 30:70 35 (ff) IP 25 >6301 >4000 72 1.730:70 35 (ff) PO 25 Blq Blq blq blq 30:70 35 (g) PO 25 231 61 28 16.130:70 35 (h) IP 25 59 46 1 1.5 30:70 35 (h) PO 50 26 7 2 * 30:70 35 (hh)PO 25 292 221 5 1.7 30:70 35 (i) PO 25 30:70 35 (j) IP 25 9531 8606 521.3 30:70 35 (j) PO 50 1328 2176 5 4.5 30:70 35 (k) IP 25 2640 2189 351.4 30:70 35 (k) PO 50 5529 4524 33 1.4 30:70 35 (m) IP 25 226 58 17 4.030:70 35 (m) PO 25 10 7 0 * 30:70 35 (n) PO 25 4818 3545 55 1.4 30:70 35(o) PO 25 683 486 3 1.0 30:70 35 (p) PO 25 1435 1958 5 1.3 30:70 35 (r)PO 25 4261 2601 67 1.3 30:70 35 (s) PO 25 7425 3371 86 2.2 30:70 35 (t)PO 25 3199 2801 41 1.1 30:70 35 (u) PO 25 30:70 35 (v) IP 25 4865 221516 0.9 30:70 35 (v) PO 50 >2946 >2000 26 1.0 30:70 35 (x) IP 25 951 78148 3.2 30:70 35 (x) PO 50 3516 2313 16 0.9 30:70 35 (y) IP 25 159 135 21.2 30:70 35 (y) PO 50 58 45 1 1.2 30:70 35 (z) IP 25 837 556 22 1.830:70 35 (z) PO 50 1001 806 14 1.6 30:70 36 (a) PO 25 605 445 17 1.530:70 37 (a) PO 25 30:70 37 (c) PO 25 2419 2338 9 1.2 30:70 39 (a) PO25 >14848 >4000 219 1.4 30:70 39 (b) PO 25 >30972 >5000 3148 11.8 30:70 4 (a) PO 50 NA 50 NA 60:40 41 (a) IP 25 92823 32202 3856 2.9 30:70 41(a) PO 50 48998 18433 2462 3.4 30:70 41 (aa) IP 25 6659 2427 124 2.160:40 41 (aa) PO 50 289 259 5 0.9 60:40 41 (b) IP 25 >5868 >1000 412 4.760:40 41 (b) PO 50 759 532 6 1.1 60:40 41 (bb) PO 50 2178 596 75 2.030:70 41 (c) IP 25 3397 2068 57 1.7 60:40 41 (c) PO 50 3182 1296 104 2.660:40 41 (d) IP 25 10324 2787 573 2.8 60:40 41 (d) PO 50 7072 2954 1501.5 60:40 41 (dd) PO 25 654 542 1 0.8 30:70 41 (e) IP 25 4900 1154 3011.6 60:40 41 (e) PO 50 302 113 7 1.6 60:40 41 (ee) IP 25 >28434 >50001670 4.0 30:70 41 (ee) PO 50 >25294 >5000 1214 3.4 30:70 41 (ff) PO 259176 2784 410 2.0 30:70 41 (g) IP 25 1925 1583 0 0.3 60:40 41 (g) PO 50508 842 1 0.7 60:40 41 (gg) PO 25 2692 2079 29 1.1 30:70 41 (h) IP 2526911 16005 300 1.2 30:70 41 (h) PO 50 4677 4080 7 0.7 30:70 41 (hh) PO25 5601 1526 405 7.9 30:70 41 (l) IP 25 1854 623 102 3.1 30:70 41 (l) PO50 212 104 0 0.5 30:70 41 (ii) PO 25 7094 1826 346 2.3 30:70 41 (j) PO25 1476 1008 17 1.3 30:70 41 (kk) PO 25 11612 3709 415 2.0 30:70 41 (m)IP 25 1864 501 54 2.3 30:70 41 (m) PO 50 9 5 0 blq 30:70 41 (mm) PO 252261 852 127 2.5 30:70 41 (n) IP 25 9408 1976 465 3.2 30:70 41 (n) PO 509066 2245 253 1.9 30:70 41 (o) IP 25 >33750 >5000 >5000 * 30:70 41 (o)PO 50 14717 4776 427 1.7 30:70 41 (p) IP 25 4150 866 380 5.5 30:70 41(q) IP 25 >27000 >4000 >4000 * 30:70 41 (q) PO 25 8572 1901 457 5.230:70 41 (r) IP 25 >23752 >5000 >5000 * 30:70 41 (r) PO50 >17789 >5000 >5000 * 30:70 41 (t) PO 25 >22498 >4000 1350 4.0 30:7041 (u) PO 25 875 224 51 5.6 30:70 41 (v) PO 25 10949 2338 749 4.4 30:7041 (x) PO 25 24174 4587 1268 4.2 30:70 41 (y) PO 25 Blq Blq blq blq30:70 42 (a) IP 25 19899 4027 1639 5.0 60:40 42 (a) PO 50 8384 3264 3412.0 60:40 42 (b) IP 25 3207 953 211 3.0 60:40 42 (b) PO 50 4747 2589 463.0 60:40 42 (d) IP 25 1774 886 31 1.4 60:40 42 (d) PO 50 46 28 18 BLQ60:40 45 (b) IP 25 11361 2636 1123 2.0 60:40 45 (b) PO 50 1636 427 1023.0 60:40 47 IP 25 236 39 29 19.9 30:70 47 PO 50 327 84 25 3.4 30:70 59(a) PO 25 50780 15878 1205 1.6 0.5% CMC 48 (a) IP 25 27000 4000 4000 *30:70 48 (a) PO 25 26636 4000 3857 * 30:70 48 (b) PO 25 2191 476 136 430:70 49 (a) PO 25 712 342 15 30:70 49 (b) PO 25 33750 5000 5000 30:70 5 (b) PO 10 61 12 3.1 60:40 59 (a) PO 8 7707 2489 122 1.5 0.5% CMC 59(a) PO 40 57240 13798 1879 2.4 0.5% CMC 59 (a) PO 200 156153 29975 121179.4 0.5% CMC 59 (b) PO 50 276467 50000 26880 CMC 59 (c) PO 25 32713550000 43090 CMC 59 (d) PO 8 >24696 >5000 1902 0.5% CMC 59 (d) PO40 >32297 >5000 4135 0.5% CMC 59 (d) PO 200 >12306 >20000 12743 0.5% CMC59 (e) PO 25 12510 28834 2135 21 0.5% CMCIn Vivo Assay of Retinal Vascular Development in Neonatal Rats

The development of the retinal vascular in rats occurs from postnatalday 1 to postnatal day 14 (P1-P14). This process is dependent on theactivity of VEGF (J. Stone, et al, J. Neurosci., 15, 4738 (1995)).Previous work has demonstrated that VEGF also acts as a survival factorfor the vessels of the retina during early vascular development (Alon,et. al, Nat. Med., 1, 1024 (1995)). To assess the ability of specificcompounds to inhibit the activity of VEGF in vivo, compounds wereformulated in an appropriate vehicle, usually 50% polyethylene glycol,average molecular weight 400 daltons, and 50% solution of 300 mM sucrosein deionized water. Typically, two microliters (2 μl) of the drugsolution was injected into the midvitreous of the eye of rat pups onpostnatal day 8 or 9. Six days after the intravitreal injection, theanimals were sacrificed and the retinas dissected free from theremaining ocular tissue. The isolated retinas were then subjected to ahistochemical staining protocol that stains endothelial cellsspecifically (Lutty and McLeod, Arch. Ophthalmol., 110, 267 (1992)),revealing the extent of vascularization within the tissue sample. Theindividual retinas are then flat-mount onto glass slides and examined todetermine the extent of vascularization. Effective compounds inhibit thefurther development of the retinal vasculature and induce a regressionof all but the largest vessels within the retina The amount of vesselregression was used to assess the relative potency of the compoundsafter in vivo administration. Vessel regression is graded on subjectivescale of one to three pluses, with one plus being detectable regressionjudged to be approximately 25 percent or less, two pluses being judgedto be approximately 25-75% regression and three pluses give to retinaswith near total regression (approximately 75% or greater).

For more quantitative analysis of regression, images of ADPase-stained,flat-mounted retinas were captured with a digital camera attached to adissecting microscope. Retinal images were then imported into an imageanalysis software (Image Pro Plus 4.0, Media Cybernetics, Silver Spring,Md.). The software was employed to determine the percentage of the areaof the retina that contained stained vessels. This value for theexperimental eye was compared to that measured for the vehicle injected,contralateral eye from the same animal. The reduction in the vasculararea seen in the eye that received compound as compared to thevehicle-injected eye was then expressed as the “percent regression” forthat sample. Percent regression values were averaged for groups of 5-8animals.

In samples in which observation through the microscope indicated neartotal regression, a percent regression value of 65-70% was routinelymeasured. This was due to stain deposits within folds of retina, foldsthat were induced by the vehicle used for drug injection. The imageanalysis software interpreted these stain-containing folds as vessels.No attempt was made to correct for these folds since they varied fromeye to eye. Thus, it should be noted that the percent regression valuesreported result from a conservative measurement that accurately rankorders compounds, but underestimates their absolute potency.

In Vivo Assay of Retinal Vascular Development in Neonatal Rat Model ofRetinopathy of Prematurity

A second model of VEGF dependent retinal neovascularization was employedto evaluate the activities of this series of compounds. In this model(Penn et. al, Invest. Ophthalmol. Vis. Sci., 36, 2063, (1995)), ratspups (n=16) with their mother are placed in a computer controlledchamber that regulates the concentration of oxygen. The animals areexposed for 24 hours to a concentration of 50% oxygen followed by 24hours at a concentration of 10% oxygen. This alternating cycle ofhyperoxia followed by hypoxia is repeated 7 times after which theanimals are removed to room air (P14). Compounds are administered viaintravitreal injection upon removal to room air and the animals aresacrificed 6 days later (P20). The isolated retinas are then isolated,stained mounted and analyzed as detail above in the development model.The effectiveness was also graded as is described for the developmentmodel.

TABLE 7 Example Initial Concen. Vehicle # Model Evaluation % Inhibition(mg/ml) PEG/water 16(e) ROP ++ 36% 5 70:30 16(e) ROP +++ 54% 10 70:3016(e) ROP ++ 37% 5 70:30 16(e) ROP +/− 16% 1 70:30 19(b) ROP ++ 10 70:3019(f) P8 +/++ 5 50:50 19(j) ROP +/− 10 70:30 19(j) ROP −− 1 70:30 19(k)ROP +/− 10 70:30 19(k) ROP −− 1 70:30 30(a) ROP ++ 10 70:30 30(a) ROP ++48% 10 70:30 31(a) P8 46% 5 70:30 31(b) P8 32% 5 50:50 31(c) P8 +/++ var5 50:50 31(d) P8 12% 5 50:50 31(e) P8 24% 5 50:50 32(a) P9 20% 5 50:5033(b) ROP ++ 55% 10 70:30 33(b) ROP +/− 14% 1 70:30 33(b) P6-P10 37% IP*70:30 33(e) P8 22% 5 70:30 33(f) P8 20% 5 50:50 35(a) P8  4% 5 50:5035(aa) P8 − 5 50:50 35(c) P8  0% 5 50:50 35(cc) P8 +/++ 5 50:50 35(dd)P8 ++/+++ var 5 50:50 35(ee) P8 +/++ 5 50:50 35(h) P8 +/− 5 50:50 35(i)P8 +/++ 5 50:50 35(j) P8 7% 5 50:50 35(k) P8 − 5 50:50 35(k) P8 ++ 550:50 35(v) P8 20% 5 50:50 38(a) ROP +++ 55% 10 70:30 38(a) ROP + 16% 170:30 39(b) P8  9% 5 50:50 4(a) ROP ++ 10 70:30 41(a) ROP +++ 64% 1070:30 41(a) P8  0% 0.5 50:50 41(a) P8  4% 1 50:50 41(a) P8 ++/+++ 550:50 41(c) ROP +++ 54% 10 70:30 41(c) ROP +/− 16% 1 70:30 41(c) P8 ++ 550:50 41(d) ROP +++ 59% 10 70:30 41(d) ROP +/−  0% 1 70:30 41(e) P8  8%5 50:50 41(ee) P8 +/++ var 5 50:50 41(g) P8 37% 5 50:50 41(h) P8  0% 570:30 41(j) P8 +/++ 5 50:50 41(k) P8  1% 5 50:50 41(l) P8 28% 2.5 70:3041(m) P8 10% 5 50:50 41(mm) P8 + 5 50:50 41(n) P8  2% 5 50:50 41(o) P8 2% 5 50:50 41(p) P8 35% 5 50:50 41(r) P8 +/++ var 5 50:50 42(a) ROP +++23% 10 70:30 42(a) ROP +  1% 1 70:30 42(a) ROP + 10 70:30 42(a) P9 55%10 70:30 42(a) P6-P10 61% IP* 70:30 42(a) P8 +/++ 5 50:50 42(b) P9 40%10 70:30 42(c) P8 36% 5 50:50 45(b) ROP ++ 60% 10 70:30 45(b) ROP +/−25% 1 70:30 49(a) P8 54% 5 50:50 49(b) P8  5% 5 50:50 5(b) ROP ++ 45% 570:30 59(a) ROP 41% 10 0.5% CMC 59(a) ROP 19% 1 0.5% CMC 6(a) ROP ++ 565:35 6(b) ROP ++ 10 70:30Phosphorylase Kinase

Phosphorylase Kinase Construct for Assay.

The truncated catalytic subunit (gamma subunit) of phosphorylase kinase(amino acids 1-298) was expressed in E. coli and isolated from inclusionbodies. Phosphorylase kinase was then refolded and stored in glycerol at−20° C.

Phosphorylase Kinase Assay. In the assay, the purified catalytic subunitis used to phosphorylate phosphorylase b using radiolabled ATP. Briefly,1.5 mg/mil of phosphorylase b is incubated with 10 nM phosphorylasekinase in 10 mM MgCl₂, 50 mM Hepes pH 7.4, at 37° C. The reaction isstarted with the addition of ATP to 100 uM and incubated for 15 min at25° C. or 37° C. The reaction was terminated and proteins wereprecipitated by the addition of TCA to 10% final concentration. Theprecipitated proteins were isolated on a 96 well Millipore MADP NOBfilter plate. The filter plate was then extensively washed with 20% TCA,and dried. Scintilation fluid was then added to the plate andincorporated radiolabel was counted on a Wallac microbeta counter. The %inhibition of phosphoryl transfer from ATP to phosphorylase b in thepresence of 10 μM of compound is shown in the Table 8 below.

TABLE 8 Example # % Inhibition @ 10 μM 52(b) 92 27(f) 90 27(a) 37

The exemplary compounds described above may be formulated intopharmaceutical compositions according to the following general examples.

Example 1 Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula I is dissolved in DMSO and then mixed with 10 mL of0.9% sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

Example 2 Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula I is mixed with 750 mg of lactose. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 3 Intraocular Composition

To prepare a sustained-release pharmaceutical composition forintraocular delivery, a compound of Formula I is suspended in a neutral,isotonic solution of hyaluronic acid (1.5% conc.) in phosphate buffer(pH 7.4) to form a 1% suspension.

It is to be understood that the foregoing description is exemplary andexplanatory in nature, and is intended to illustrate the invention andits preferred embodiments. Through routine experimentation, the artisanwill recognize apparent modifications and variations that may be madewithout departing from the spirit of the invention. Thus, the inventionis intended to be defined not by the above description, but by thefollowing claims and their equivalents.

1. A method to prepare a compound or a salt of formula I,

wherein R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R² is Y—X, where Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, orN-C₁-C₈ alkyl); X is

 where R⁹ is a substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl,NH—(C₁-C₈ alkyl), NH-(aryl), NH-(heteroaryl), N═CH-(alkyl), NH(C═O)R¹¹,or NH₂, where R¹¹ is selected from hydrogen, substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;and R¹⁰ is independently selected from hydrogen, halogen, andlower-alkyl; the method comprising converting a compound of formula IXinto a compound of formula X by a cross coupling reaction in thepresence of a metal catalyst or a stoichiometric metal reagent:

where Pg is a protecting group; and removing the protecting group toform the compound of formula I.
 2. The method of claim 1, wherein thestep of converting the compound of formula IX to the compound of formulaX comprises: (i) reacting the compound of formula IX with a nucleophilicR² compound in the presence of a metal catalyst; or (ii) treating thecompound of formula IX with a stochiometric organometallic reagent in ahalogen-metal exchange reaction to form a metal containing intermediate,and treating the intermediate with an electrophilic R² compound to formthe compound of formula X.
 3. The method of claim 1, wherein the Pg is1-(2-trimethylsilanyl-ethoxymethyl).
 4. The method of claim 2, whereinthe nucleophilic R² compound is an R²-boronic acid.
 5. The method ofclaim 2, wherein the organometallic reagent is an organolithiumcompound.
 6. The method of claim 1, wherein the compound of formula IXis prepared by treating the compound of formula VIII with an oxidizingreagent and a halogenating reagent:


7. The method of claim 6, wherein the oxidizing reagent is a nitritecompound.
 8. The method of claim 6, wherein the compound of formula VIIIis prepared from a compound of formula VII by reducing the nitro groupof the compound of formula VII to the amino group of the compound offormula VIII


9. The method of claim 8, wherein the step of reducing the nitro groupis carried out in the presence of SnCl₂.
 10. The method of claim 8,wherein the compound of formula VII is prepared from a compound offormula VI by a metal catalyzed cross coupling reaction


11. The method of claim 10, wherein the metal catalyzed cross couplingreaction is carried out in the presence of an R¹-organometallic reagentand a catalyst.
 12. The method of claim 11, wherein theR¹-organometallic reagent is an R¹-boronic acid and the catalyst is apalladium catalyst.
 13. The method of claim 10, wherein the compound offormula VI is prepared from a compound of formula V

by a process that comprises: treating the compound of formula V with astrong base and an iodination reagent to form an intermediate; andsubsequently treating the intermediate with a strong base and aPg-halide.
 14. The method of claim 13, wherein the Pg-halide is1-(2-trimethylsilanyl-ethoxymethyl) chloride.
 15. A method to prepare acompound or a salt of formula I,

wherein R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R² is Y—X, where Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, orN-(C₁-C₈ alkyl); X is

 where R⁹ is a substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl,NH—(C₁-C₈ alkyl), NH-(aryl), NH-(heteroaryl), N═CH-(alkyl), NH(C═O)R¹¹,or NH₂, where R¹¹ is selected from hydrogen, substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;and R¹⁰ is independently selected from hydrogen, halogen, andlower-alkyl; the method comprising converting a compound of formula XIVinto a compound of formula XV by a metal catalyzed cross couplingreaction:

where Pg is a protecting group; and removing the protecting group toform the compound of formula I.
 16. The method of claim 15, wherein themetal catalyzed cross coupling reaction is carried out by treating thecompound of formula XIV with an R¹-organometallic reagent in thepresence of a metal catalyst.
 17. The method of claim 16, wherein theR¹-organometallic reagent is an R¹-boronic acid or an R¹—ZnCl, and themetal catalyst is a palladium catalyst.
 18. The method of claim 15,wherein the compound of formula XIV is prepared from a compound offormula XIII by a metal catalyzed cross coupling reaction:


19. The method of claim 18, wherein the metal catalyzed cross couplingreaction is carried out by treating the compound of formula XIII with anR²-organometallic reagent in the presence of a metal catalyst.
 20. Themethod of claim 19, wherein the R²-organometallic reagent is anR²-boronic acid reagent, or a R²—ZnCl reagent, and the metal catalyst isa palladium catalyst.
 21. The method of claim 18, wherein the compoundof formula XIII is prepared by reacting a compound of formula XII with aprotecting group reagent:


22. The method of claim 21, wherein the protecting group reagent is1-(2-trimethylsilanyl-ethoxymethyl) chloride.
 23. The method of claim21, wherein the compound of formula XII is prepared from a compound offormula XI by an iodination reaction:


24. The method of claim 23, wherein the iodination reaction is carriedout by treating the compound of formula XI with I₂ in the presence of astrong base.
 25. A method to prepare a compound or a salt of formula I,

wherein R¹ is a substituted or unsubstituted aryl or heteroaryl, or agroup of the formula CH═CH—R³ or CH═N—R³, where R³ is a substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R² is Y—X, where Y is O, S, C═CH₂, C═O, S═O, SO₂, CH₂, CHCH₃, NH, orN-(C₁-C₈ alkyl); X is

 where R⁹ is a substituted or unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl,NH-(C₁-C₈ alkyl), NH-(aryl), NH-(heteroaryl), N═CH-(alkyl), NH(C═O)R¹¹,or NH₂, where R¹¹ is selected from hydrogen, substituted orunsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;and R¹⁰ is independently selected from hydrogen, halogen, andlower-alkyl; the method comprising dehydrogenation of a compound offormula XVIII to form the compound of formula I:


26. The method of claim 25, wherein the dehydrogenation reaction iscarried out by treating the compound of formula XVIII with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
 27. The method of claim25, wherein the compound of formula XVIII is prepared by an annulationreaction of a 1,3-diketone compound of formula XVII:


28. The method of claim 27, wherein the annulation reaction is carriedout in the presence of hydrazine.
 29. The method of claim 27, whereinthe compound of formula XVII is prepared from a compound of formula XVIby an acylation reaction:


30. The method of claim 29, wherein the acylation reaction is carriedout by treating a compound of formula XVI with a strong base and anacylation reagent LCO-R¹, where L is a leaving group.
 31. The method ofclaim 29, wherein the compound of formula XVI is prepared from acompound of formula XV by a nucleophilic substitution reaction


32. The method of claim 31, wherein the nucleophilic substitutionreaction is carried out by contacting the compound of formula XV with astrong base and a nucleophile R²—H.